Circulating tumor cells (CTCs) serve as valuable biomarkers in tumor circulation, carrying essential primary tumor information. The purification of CTCs from peripheral blood samples and the analysis of their characteristic molecules enable the detection of tumors at an early stage. The noninvasive, continuous, real-time dynamic monitoring provides a promising solution for the timely diagnosis of colorectal cancer (CRC). In this study, we developed a minimally invasive method for CRC early detection to enable accurate screening in a friendly manner for individuals who generally require colonoscopy. The dual-antibody (i.e., anti-EpCAM and anti-EGFR) modified antifouling hydrogel-coated magnetic nanoparticles (pSBMA-MNPs) were prepared for efficient and specific CTC purification. Then, the quantification of 6 RNA transcripts in purified CRC CTCs was performed via droplet digital PCR (ddPCR), and a CRC score was calculated using an extreme gradient boosting model to distinguish CRC from colon polyps and adenomas. A pilot study was conducted to evaluate the clinical potential of the CRC CTC RNA assay in a training cohort (n = 101) and an independent test cohort (n = 65), achieving a diagnostic accuracy of 91.0% in the whole cohort, significantly outperforming serum CEA, CA125, and CA199. Subgroup analysis across CRC stage, age, and tumor location of patients was also performed, and the CRC score exhibited robust performance, demonstrating commendable diagnostic efficacy for CRC detection and promising application in friendly screening individuals that really require colonoscopy.

Despite apparently curative treatment, many patients with colorectal cancer develop subsequent metastatic disease. Current prognostic models are criticised because they are based on standard staging and omit novel biomarkers. Improved prognostication is an unmet need.

To improve prognostication for colorectal cancer by developing a baseline multivariable model of standard clinicopathological predictors, and to then improve prediction via addition of promising novel imaging, genetic and immunohistochemical biomarkers.

Prospective multicentre cohort.

Thirteen National Health Service hospitals.

Consecutive adult patients with colorectal cancer.

Collection of prespecified standard clinicopathological variables and more novel imaging, genetic and immunohistochemical biomarkers, followed by 3-year follow-up to identify postoperative metastasis.

Best multivariable prognostic model including perfusion computed tomography compared with tumour/node staging. Secondary outcomes: Additive benefit of perfusion computed tomography and other biomarkers to best baseline model comprising standard clinicopathological predictors; measurement variability between local and central review; biological relationships between perfusion computed tomography and pathology variables.

Between 2011 and 2016, 448 participants were recruited; 122 (27%) were withdrawn, leaving 326 (226 male, 100 female; mean ± standard deviation 66 ± 10.7 years); 183 (56%) had rectal cancer. Most cancers were locally advanced [≥ T3 stage, 227 (70%)]; 151 (46%) were node-positive (≥ N1 stage); 306 (94%) had surgery; 79 (24%) had neoadjuvant therapy. The resection margin was positive in 15 (5%); 93 (28%) had venous invasion; 125 (38%) had postoperative adjuvant chemotherapy; 81 (25%, 57 male) developed recurrent disease. Prediction of recurrent disease by the baseline clinicopathological time-to-event Weibull multivariable model (age, sex, tumour/node stage, tumour size and location, treatment, venous invasion) was superior to tumour/node staging: sensitivity: 0.57 (95% confidence interval 0.45 to 0.68), specificity 0.74 (95% confidence interval 0.68 to 0.79) versus sensitivity 0.56 (95% confidence interval 0.44 to 0.67), specificity 0.58 (95% confidence interval 0.51 to 0.64), respectively. Addition of perfusion computed tomography variables did not improve prediction significantly: c-statistic: 0.77 (95% confidence interval 0.71 to 0.83) versus 0.76 (95% confidence interval 0.70 to 0.82). Perfusion computed tomography parameters did not differ significantly between patients with and without recurrence (e.g. mean ± standard deviation blood flow of 60.3 ± 24.2 vs. 61.7 ± 34.2 ml/minute/100 ml). Furthermore, baseline model prediction was not improved significantly by the addition of any novel genetic or immunohistochemical biomarkers. We observed variation between local and central computed tomography measurements but neither improved model prediction significantly. We found no clear association between perfusion computed tomography variables and any immunohistochemical measurement or genetic expression.

The number of patients developing metastasis was lower than expected from historical data. Our findings should not be overinterpreted. While the baseline model was superior to tumour/node staging, any clinical utility needs definition in daily practice.

A prognostic model of standard clinicopathological variables outperformed tumour/node staging, but novel biomarkers did not improve prediction significantly. Biomarkers that appear promising in small single-centre studies may contribute nothing substantial to prognostication when evaluated rigorously.

It would be desirable for other researchers to externally evaluate the baseline model.

This trial is registered as ISRCTN95037515.

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/22/49) and is published in full in Health Technology Assessment; Vol. 29, No. 8. See the NIHR Funding and Awards website for further award information.

Nanotechnology has revolutionized cancer diagnostics and therapy, offering unprecedented possibilities to overcome the constraints of conventional treatments. This study provides a detailed overview of the current progress and difficulties in the creation of nanostructured materials, with a specific emphasis on their use in drug and gene delivery systems. The study examines tactics that attempt to improve the effectiveness and safety of chemotherapeutic drugs such as doxorubicin (Dox) by focusing on the potential of antibody-drug conjugates and functionalized nanoparticles. Moreover, it clarifies the challenges encountered in administering nanoparticles orally for gastrointestinal treatments, emphasizing the crucial physicochemical properties that affect their behavior in the gastrointestinal system. This study highlights the transformational potential of nanostructured materials in precision oncology by examining advanced breakthroughs such cell membrane-camouflaged nanoparticles and inorganic nanoparticles designed for gastrointestinal disorders. The text investigates the processes involved in the absorption of nanoparticles and their destruction in lysosomes, revealing the many methods in which enterocytes take up these particles. This study strongly supports the use of advanced nanoparticle-based methods to reduce the harmful effects on the whole body and improve the effectiveness of therapy, based on a thorough examination of current experiments on animals and humans. The main objective of this paper is to provide a fundamental comprehension that will stimulate more investigation and practical use in the field of cancer nanomedicine, advancing its boundaries.

Cancer-derived small extracellular vesicles (sEVs) in body fluids hold promise as biomarkers for cancer diagnosis. For sEV-based liquid biopsy, isolation of sEVs with a high-purity and cancer-sEV detection with an extremely high sensitivity are essential because body fluids include much higher density of normal-cell-derived sEVs and other biomolecules and bioparticles. Here, we propose an isolation-analysis-integrated cancer-diagnosis platform based on dielectrophoresis(DEP)-ELISA technique which enables a three orders of magnitude higher sensitivity over conventional ELISA method and direct cancer diagnosis from blood plasma with high accuracy. The limit of detection (LOD) for sEVs in human plasma was as low as 104 sEVs/mL without a time-consuming and low-yield sEV isolation and purification process. The capability of this platform was validated by monitoring mice with cancer cell inoculation and assessing the effect of cancer-sEV-inhibiting drug. Using the developed sEV-based liquid biopsy, we diagnosed clinical samples from healthy donors (N = 39) and cancer patients (N = 90). The diagnostic accuracy was 94.2%, 98.6%, and 91.3% for breast, colon, and lung cancers, respectively. This integrated sEV isolation and analysis platform could be applied for high-sensitivity biomarker profiling and sEV-based liquid biopsy.

Gasdermin D (GSDMD) is a key effector molecule that activates pyroptosis through its N terminal domain (GSDMD-NT). However, the roles of GSDMD in colorectal cancer (CRC) have not been fully explored. The role of the full-length GSDMD (GSDMD-FL) is also not clear. In this study, we observed that GSDMD modulates CRC progression through other mechanisms in addition to activating GSDMD-NT.

Clinical CRC samples and human-derived CRC cell lines were used in this study. GSDMD expression was evaluated by RT-qPCR, Western blot and immunohistochemical (IHC) analysis. GSDMD knockdown and overexpression stable cell lines were established by Lentiviral transduction. CCK-8 assay, flow cytometry analysis for cell cycle, Transwell assay, and cell scratch assay were performed in vitro to explore the impact of GSDMD on CRC progression. Mouse subcutaneous transplantation tumor models were constructed to assess the role of GSDMD in vivo. Intestinal epithelial cell (IEC)-specific knockout of Gsdmd mice (GsdmdΔIEC) was used to evaluate the effect of GSDMD on intestinal adenoma formation in AOM-DSS and Apcmin/+ mouse models. RNA sequencing was performed to explore the regulatory pathways associated with the role of GSDMD in CRC cells. Co-Immunoprecipitation (CO-IP), Western blot and immunofluorescence (IF) were conducted to investigate the interactions between GSDMD and EGFR. Exogenous addition of Gefitinib was used to evaluate the effect of GSDMD on autophosphorylation of EGFR at the Tyr1068 site.

GSDMD was highly expressed in clinical CRC tissues and human-derived CRC cell lines. GSDMD knockdown inhibited the viability, cell cycle changes, invasion ability and migration ability of CRC cell lines in vitro and vivo, whereas GSDMD overexpression had the opposite effects. Intestinal adenoma development was reduced in GsdmdΔIEC mice in both AOM-DSS and Apcmin/+ mouse models. GSDMD-FL interacted with EGFR and promoted CRC progression by inducing autophosphorylation of EGFR at the Tyr1068 site, subsequently activating ERK1/2. Exogenous Gefitinib abrogated the tumorigenic properties of GSDMD.

GSDMD-FL promotes CRC progression by inducing EGFR autophosphorylation at the Tyr1068 site, subsequently activating the downstream ERK1/2. Inhibition of GSDMD is a potential strategy for the treatment of colorectal cancer.

Lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), is the most prevalent cancer globally and remains the leading cause of cancer-related mortality. Epidermal growth factor receptor (EGFR) mutations, frequently observed in female NSCLC patients, have revolutionized treatment strategies with the advent of tyrosine kinase inhibitors (TKIs). These therapies significantly improve survival and are considered the standard of care for patients harboring EGFR mutations. However, most patients eventually develop resistance to EGFR-TKIs, leading to disease progression. Resistance mechanisms are classified as either EGFR-dependent or EGFR-independent, the latter involving bypass pathway activation, including dysregulation of downstream signaling cascades. EGFR-independent resistance often renders all EGFR-TKIs ineffective, necessitating further investigation into resistance mechanisms.

We report the case of a 63-year-old Chinese woman diagnosed with synchronous lung adenocarcinoma harboring an EGFR exon 21 far-loop insertion mutation and clear cell renal cell carcinoma (ccRCC). A multidisciplinary team recommended systemic therapy for the lung adenocarcinoma and clinical observation for ccRCC. First-line treatment with bevacizumab plus pemetrexed-carboplatin achieved a progression-free survival (PFS) of 7 months. Second-line treatment with sintilimab and nedaplatin resulted in a PFS of 4.9 months. Third-line therapy with sintilimab and anlotinib proved ineffective. In the fourth line, the patient received furmonertinib, a third-generation EGFR-TKI, based on the FAVOUR trial. This treatment achieved durable disease control with excellent tolerability, yielding a PFS of 27 months and ongoing clinical benefit.

This case demonstrates that furmonertinib can provide significant clinical benefit to NSCLC patients with complex resistance mechanisms, including those involving the PIK3CA/mTOR pathway. These findings support its potential to overcome EGFR-TKI resistance and warrant further investigation in similar clinical contexts.

Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody drug conjugate that has remarkable activity in HER2-positive cancers. However, the degree of benefit of T-DXd is not uniform among solid tumors even with high levels of HER2. Despite high HER2 expression, the HER2/T-DXd complex may not always undergo internalization and payload release dependent on the receptor's conformation and context. We hypothesize that epidermal growth factor receptor (EGFR), a dimerization partner of HER2, can modulate HER2 trafficking through endocytic pathways and affect T-DXd uptake. We demonstrate that elevated EGFR expression levels can promote EGFR/HER2 heterodimer formation and suppress T-DXd internalization and efficacy. Knockdown of EGFR expression or pharmacologic stimulation of EGFR endocytosis with EGFR monoclonal antibodies restores T-DXd trafficking and antitumor activity in EGFR-overexpressing cancers in vivo. Our results reveal EGFR overexpression to be a potential mechanism of resistance to T-DXd, which can be overcome by combination therapy strategies targeting EGFR.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.

Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.

In our quest to find improved anticancer therapeutics, we expedite the lead optimization of (E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (6b), an EGFR inhibitor previously discovered in our laboratory through an in-house screening program. The lead optimization was rationally initiated considering the catalytic site of EGFR. We synthesized twenty-nine new analogues of 6b and assessed their anticancer activities. SAR studies highlighted the role of important groups in controlling anticancer activities. Among all, 5a and 5l were found to exhibit improved EGFR inhibition with anticancer asset potential. In silico studies corroborated with in vitro EGFR inhibitory results. The deeper analysis of 5a and 5l revealed that these synthetics could alter the MMP (ΔΨ m) and significantly reduce the ROS levels in lung cancer cells. This is a vital prerequisite for better plausible EGFR inhibitors devoid of cardiotoxicity. qPCR analysis further revealed that the investigational compounds 5a and 5l were able to downregulate the expression of key oncogenes, viz., KRAS, MAP2K, and EGFR. The downregulation of these genes suggests that the investigational compounds could interact and inhibit key players in the signalling cascade along with the EGFR, which may lead to the inhibition of the growth and prognosis of cancer cells via a holistic approach.

Colorectal cancer (CRC) is one of the most diagnosed cancers and a leading contributor to cancer-related deaths in the United States. Clinically, standard treatment regimens include surgery, radiation, and chemotherapy; however, there has been increasing development and clinical use of targeted therapies for CRC. Unfortunately, many patients develop resistance to these treatments. Cetuximab, the first targeted therapy approved to treat advanced CRC, is a monoclonal antibody that targets the epidermal growth factor receptor and inhibits downstream pathway activation to restrict tumor cell growth and proliferation. CRC resistance to cetuximab has been well studied, and common resistance mechanisms include constitutive signal transduction through downstream protein mutations and promotion of the epithelial-to-mesenchymal transition. While the most common resistance mechanisms are known, a proportion of patients develop resistance through unknown mechanisms. One protein predicted to contribute to therapy resistance is RAC1, a small GTPase that is involved in cytoskeleton rearrangement, cell migration, motility, and proliferation. RAC1 has also been shown to be overexpressed in CRC. Despite evidence that RAC1 and its alternative splice isoform RAC1B play important roles in CRC and the pathways known to contribute to cetuximab resistance, there is a need to directly study the relationship between RAC1 and RAC1B and cetuximab resistance. This review highlights the recent studies investigating RAC1 and RAC1B in the context of CRC and suggests that these proteins could play a role in resistance to cetuximab.

Ovarian cancer is one of women's malignancies with the highest mortality among gynecological cancers. Paclitaxel is used in first-line ovarian cancer chemotherapy. Research on paclitaxel-resistant ovarian cancer holds significant clinical importance.

Cell viability and flow cytometric assays were conducted at different time and concentration points of deguelin and paclitaxel treatment. Immunoblotting was performed to assess the activation status of key signaling molecules important for cell survival and proliferation following treatment with deguelin and paclitaxel. The fluo-3 acetoxymethyl assay for P-glycoprotein transport activity assay and cell viability assay in the presence of N-acetyl-L-cysteine were also conducted.

Cell viability and flow cytometric assays demonstrated that deguelin resensitized paclitaxel in a dose- and time-dependent manner. Cotreatment with deguelin and paclitaxel inhibited EGFR and its downstream signaling molecules, including AKT, ERK, STAT3, and p38 MAPK, in SKOV3-TR cells. Interestingly, cotreatment with deguelin and paclitaxel suppressed the expression level of EGFR via the lysosomal degradation pathway. Cotreatment did not affect the expression and function of P-glycoprotein. N-acetyl-L-cysteine failed to restore cell cytotoxicity when used in combination with deguelin and paclitaxel in SKOV3-TR cells. The expression of BCL-2, MCL-1, and the phosphorylation of the S155 residue of BAD were downregulated. Moreover, inhibition of paclitaxel resistance by deguelin was also observed in HeyA8-MDR cells.

Our research showed that deguelin effectively suppresses paclitaxel resistance in SKOV3-TR ovarian cancer cells by downregulating the EGFR and its downstream signaling pathway and modulating the BCL-2 family proteins. Furthermore, deguelin exhibits inhibitory effects on paclitaxel resistance in HeyA8-MDR ovarian cancer cells, suggesting a potential mechanism for paclitaxel resensitization that may not be cell-specific. These findings suggest that deguelin holds promise as an anticancer therapeutic agent for overcoming chemoresistance in ovarian cancer.

The EGFR/PI3K/Akt/mTOR pathway is important for metastasis, medication resistance, apoptosis prevention, and malignant transformation. Mutations in lung and colon cancer typically change this pathway's expression. As a result, a novel class of 1,2,4-oxdiazoles that are attached to 1,2,3-triazoles, 5-11, were created as possible anticancer drugs. The produced compounds are all examined by spectroscopic and micro-analytical techniques. MTT assay results on lung (A549) colon (Caco-2) and normal lung fibroblast (WI38) revealed that compounds 6a, 6b, 8a, and 11b demonstrated strong and selective antiproliferative activities against lung (A549) and colon (Caco-2) cancer cell lines while the remaining derivatives showed moderate to low activity. qPCR data revealed that the potential hits had large fold changes in the downregulation of EGFR, mTOR, and PI3K; they upregulate the amount of p53 to support their mode of action even more. Interestingly, docking investigations validated the biological outcomes by demonstrating a strong affinity of our compounds against EGFR active regions. Computational predictions of all the synthesized compounds' pharmacokinetic profiles, physicochemical characteristics, and drug-likeness data indicated that the promising hits might be taken into consideration as drug-like prospects.

We have semi-synthesized a natural product 7-acetylhorminone from crude extract of Premna obtusifolia (Indian headache tree), which is active against colorectal cancer after probation through computational screening methods as it passed through the set parameters of pharmacokinetics (most important nonblood-brain barrier permeant) and drug likeliness (e.g., Lipinski's, Ghose's, Veber's rule) which most other phytoconstituents failed to pass combined with docking with EGFR protein which is highly upregulated in the colorectal carcinoma cell. The structure of 7-acetylhorminone was confirmed by single crystal X-ray diffraction studies and 1H NMR, 13C NMR, and COSY studies. To validate the theoretical studies, first, in vitro experiments were carried out against human colorectal carcinoma cell lines (HCT116) which revealed the potent cytotoxic efficacy of 7-acetylhorminone and verified preliminary investigation. Second, the drugability of 7-acetylhorminone interaction with serum albumin proteins (HSA and BSA) is evaluated both theoretically and experimentally via steady-state fluorescence spectroscopic studies, circular dichroism, isothermal titration calorimetry, and molecular docking. In summary, this study reveals the applicability of 7-acetylhorminone as a potent drug candidate or as a combinatorial drug against colorectal cancer.

The aim of this study was to design and examine a novel epidermal growth factor receptor (EGFR) inhibitor with apoptotic properties by utilizing the essential structural characteristics of existing EGFR inhibitors as a foundation.

The study began with the natural alkaloid theobromine and developed a new semisynthetic derivative (T-1-PMPA). Computational ADMET assessments were conducted first to evaluate its anticipated safety and general drug-likeness. Deep density functional theory (DFT) computations were initially performed to validate the three-dimensional (3D) structure and reactivity of T-1-PMPA. Molecular docking against the EGFR proteins was conducted to investigate T-1-PMPA's binding affinity and inhibitory potential. Additional molecular dynamics (MD) simulations over 200 ns along with MM-GPSA, PLIP, and principal component analysis of trajectories (PCAT) experiments were employed to verify the binding and inhibitory properties of T-1-PMPA. Afterward, T-1-PMPA was semisynthesized to validate the proposed design and in silico findings through several in vitro examinations.

DFT studies indicated T-1-PMPA's reactivity using electrostatic potential, global reactive indices, and total density of states. Molecular docking, MD simulations, MM-GPSA, PLIP, and ED suggested the binding and inhibitory properties of T-1-PMPA against the EGFR protein. The in silico ADMET predicted T-1-PMPA's safety and general drug-likeness. In vitro experiments demonstrated that T-1-PMPA effectively inhibited EGFRWT and EGFR790m, with IC50 values of 86 and 561 nM, respectively, compared to Erlotinib (31 and 456 nM). T-1-PMPA also showed significant suppression of the proliferation of HepG2 and MCF7 malignant cell lines, with IC50 values of 3.51 and 4.13 μM, respectively. The selectivity indices against the two cancer cell lines indicated the overall safety of T-1-PMPA. Flow cytometry confirmed the apoptotic effects of T-1-PMPA by increasing the total percentage of apoptosis to 42% compared to 31, and 3% in Erlotinib-treated and control cells, respectively. The qRT-PCR analysis further supported the apoptotic effects by revealing significant increases in the levels of Casp3 and Casp9. Additionally, T-1-PMPA controlled the levels of TNFα and IL2 by 74 and 50%, comparing Erlotinib's values (84 and 74%), respectively.

In conclusion, our study's findings suggest the potential of T-1-PMPA as a promising apoptotic anticancer lead compound targeting the EGFR.

The molecular characterization of male breast cancer (MaBC) has received limited attention in research, mostly because of its low incidence rate, accounting for only 0.5% to 1% of all reported cases of breast cancer each year. Managing MaBC presents significant challenges, with most treatment protocols being adapted from those developed for female breast cancer. Utilizing whole-genome sequencing (WGS) and state-of-the-art analyses, the genomic features of 10 MaBC cases (n = 10) were delineated and correlated with clinical and histopathologic characteristics. Using fluorescence in situ hybridization, an additional cohort of 18 patients was interrogated to supplement WGS findings. The genomic landscape of MaBC uncovered significant genetic alterations that could influence diagnosis and treatment. We found common somatic mutations in key driver genes, such as FAT1, GATA3, SMARCA4, and ARID2. Our study also mapped out structural variants that impact cancer-associated genes, such as ARID1A, ESR1, GATA3, NTRK1, and NF1. Using a WGS-based classifier, homologous recombination deficiency (HRD) was identified in 2 cases, both presenting with deleterious variants in BRCA2. Noteworthy was the observation of FGFR1 amplification in 21% of cases. Altogether, we identified at least 1 potential therapeutic target in 8 of the 10 cases, including high tumor mutational burden, FGFR1 amplification, and HRD. Our study is the first WGS characterization of MaBC, which uncovered potentially relevant variants, including structural events in cancer genes, HRD signatures, and germline pathogenic mutations. Our results demonstrate unique genetic markers and potential treatment targets in MaBC, thereby underlining the necessity of tailoring treatment strategies for this understudied patient population. These WGS-based findings add to the growing knowledge of MaBC genomics and highlight the need to expand research on this type of cancer.

Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver disease (NAFLD) are at a greater risk of developing liver metastasis. With the growing prevalence of NAFLD, a better understanding of the molecular mechanism in NAFLD-driven CRC liver metastasis is needed. In this study, we demonstrated that NAFLD facilitated CRC liver metastasis as a metabolic disorder and promoted the stemness of metastatic CRC cells for their colonization and outgrowth in hepatic niches. Metabolically, the lipid-rich microenvironment in NAFLD activated de novo palmitate biosynthesis in metastatic CRC cells via upregulating fatty acid synthase (FASN). Moreover, increased intracellular palmitate bioavailability promoted EGFR palmitoylation to enhance its protein stability and plasma membrane localization. Furthermore, we demonstrated that the FDA-approved FASN inhibitor orlistat could reduce NAFLD-activated endogenous palmitate production, thus inhibiting palmitoylation of EGFR to suppress CRC cell stemness and restrict liver metastasis in synergy with conventional chemotherapy. These findings reveal that the NAFLD metabolic microenvironment boosts endogenous palmitate biosynthesis in metastatic CRC cells and promotes cell stemness via EGFR palmitoylation, and FASN inhibitor orlistat could be a candidate adjuvant drug to suppress liver metastasis in CRC patients with NAFLD.

It is well established that most colorectal carcinomas arise from conventional adenomas through the adenoma-carcinoma sequence (ACS) model. mitogen-activated protein kinases (MAPKs) pathway has been reported as a crucial player in tumorigenesis. The MAPK signaling pathway is activated by different extracellular signals involving the "mitogen-activated/extracellular signal-regulated kinase 1 (MEK1)", and this induces the expression of genes involved in proliferation and cellular transformation. Diaphanous-related formin-3 (DIAPH3) acts as a potential metastasis regulator through inhibiting the cellular transition to amoeboid behavior in different cancer types.

The aim of the study was to investigate the pattern of immunohistochemical expression of MEK1 and DIAPH3 in colorectal adenoma (CRA) and corresponding colorectal carcinoma (CRC) specimens.

The immunohistochemical expression of DIAPH3 and MEK1 was examined in 43 cases of CRC and their associated adenomas using tissue microarray technique.

MEK1 was overexpressed in 23 CRC cases (53.5%) and in 20 CRA cases (46.5%). DIAPH3 was overexpressed in 11 CRA cases (about 29%) which were significantly lower than CRC (22 cases; 58%) (P = 0.011). Both MEK1 and DIAPH3 overexpression were significantly correlated in CRC (P = 0.009) and CRA cases (P = 0.002). Tumors with MEK1 overexpression had a significantly higher tumor grade (P = 0.050) and perineural invasion (P = 0.017).

Both MEK1 and DIAPH3 are overexpressed across colorectal ACS with strong correlation between them. This co- expression suggests a possible synergistic effect of MEK1 and DIAPH-3 in colorectal ACS. Further large-scale studies are required to investigate the potential functional aspects of MEK1 and DIAPH3 in ACS and their involvement in tumor initiation and the metastatic process.

Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.

Immunotherapy for colorectal cancer (CRC) is limited to patients with advanced disease who have already undergone first-line chemotherapy and whose tumors exhibit microsatellite instability. Novel technical strategies are required to enhance therapeutic options and achieve a more robust immunological response. Therefore, exploring gene analysis and manipulation at the molecular level can further accelerate the development of advanced technologies to address these challenges. The emergence of advanced genome editing technology, particularly of clustered, regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) 9, holds promise in expanding the boundaries of cancer immunotherapy. In this manuscript, we provide a comprehensive review of the applications and perspectives of CRISPR technology in improving the design, generation, and efficiency of current immunotherapies, focusing on solid tumors such as colorectal cancer, where these approaches have not been as successful as in hematological conditions.

Colorectal cancer (CRC) is considered the second deadliest cancer in the world. One of the reasons for the occurrence of this cancer is the deregulation of the Epidermal Growth Factor Receptor (EGFR), which plays a critical role in regulating cell division, persistence, differentiation, and migration. The overexpression of the EGFR protein leads to its dysregulation and causes CRC.

Hence, this work aims to identify and validate novel EGFR inhibitors for the treatment of colorectal cancer employing various computer aided techniques such as pharmacophore modeling, docking, molecular dynamic simulation and Quantitative Structure-Activity Relationship (QSAR) analysis.

In this work, a shared-featured ligand-based pharmacophore model was generated using the known inhibitors of EGFR. The best model was validated and screened against ZincPharmer and Maybridge databases, and 143 hits were obtained. Pharmacokinetic and toxicological properties of these hits were studied, and the acceptable ligands were docked against EGFR. The best five protein-ligand complexes with binding energy less than -5 kcal/mol were selected. The molecular dynamic simulation studies of these complexes were conducted for 100 nanoseconds (ns), and the results were analyzed. The biological activity of this ligand was calculated using QSAR analysis.

The best complex with Root Mean Square Deviation (RMSD) 3.429 Å and Radius of Gyration (RoG) 20.181 Å was selected. The Root Mean Square Fluctuations (RMSF) results were also found to be satisfactory. The biological activity of this ligand was found to be 1.38 μM.

This work hereby proposes the ligand 2-((1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)oxy)-N- (1H-indol-4-yl)acetamide as a potential EGFR inhibitor for the treatment of colorectal cancer. The wet lab analysis must be conducted, however, to confirm this hypothesis.

Receptor tyrosine kinases (RTKs) are a class of protein kinases that play crucial roles in various cellular processes, including cell migration, morphological differentiation, cell growth, and angiogenesis. In humans, 58 RTKs have been identified and categorized into 20 distinct families based on the composition of their extracellular regions. RTKs are primarily activated by specific ligands that bind to their extracellular region. They not only regulate tumor transformation, proliferation, metastasis, drug resistance, and angiogenesis, but also initiate and maintain the self-renewal and cloning ability of cancer stem cells. Accurate diagnosis and grading of tumors with dysregulated RTKs are essential in clinical practice. There is a growing body of evidence supporting the benefits of RTKs-targeted therapies for cancer patients, and researchers are actively exploring new targets and developing targeted agents. However, further optimization of RTK inhibitors is necessary to effectively target the diverse RTK alterations observed in human cancers. This review provides insights into the classification, structure, activation mechanisms, and expression of RTKs in tumors. It also highlights the research advances in RTKs targeted anticancer therapy and emphasizes their significance in optimizing cancer diagnosis and treatment strategies.

Colorectal cancer (CRC) is considered the result of the cumulative effect of multiple mutations within the cell that allow it to escape growth control and regulatory mechanisms. EGFR overexpression has been suggested as a factor of poor prognosis in various cancers. β-catenin plays a role in the Wnt signaling pathway of colorectal cancers. An analytical cross-sectional study was conducted over a period of two years comprising 20 colectomy specimens. Clinicopathological details were documented, and immunohistochemistry (IHC) for EGFR and β-catenin was performed. EGFR-Brown membranous staining was observed; β-catenin-Brown membranous or nuclear staining was observed. IHC scoring was done, taking into account the intensity of staining and the percentage of positive tumor cells. The mean age of patients with colorectal carcinoma was 47.45 ± 14.8 (mean + SD) years. No statistically significant difference was noted in the EGFR immunoexpression and tumor grade (p value = 0.361) as well as the TNM stage (p value = 0.699). There was no statistically significant difference between β-catenin immunoexpression and tumor grade (p value = 0.444) and TNM stage (p value = 0.911). A statistically significant difference was noted in the EGFR and β-catenin immunoexpression (p = 0.0001). EGFR and β-catenin expression was observed in 50% and 65% of cases, respectively. EGFR and β-catenin expression was not associated with histological tumor grade and TNM stage of the tumor. In the present study, EGFR expression was significantly associated with β-catenin immunoexpression.

Cadmium (Cd) is a hazardous environmental heavy metal with a prolonged biological half-life. Due to the main route of foodborne exposure, the intestinal tract is particularly vulnerable to Cd-induced toxicity. However, the chronic toxicity and underlying mechanisms of Cd in intestinal diseases, including colorectal cancer (CRC), still remain vague. Herein, we aim to investigate the long-term effects of Cd exposure on CRC development and the key signaling event. Our findings indicate that chronic and low-dose exposure to Cd promoted the invasion and metastasis capability of CRC cells in vitro and in mice, with a marginal increase in cell growth. The expression of cell junction-related genes was down-regulated while those molecules that facilitate cell mobility were significantly increased by Cd exposure. Epidermal growth factor receptor (EGFR) signaling was identified to play the dominant role in Cd-promoted CRC metastasis. Interestingly, Cd activated EGFR in a non-canonical manner that exhibited distinct signaling dynamics from the canonical ligand. In contrast to EGF, which induced transient EGFR signaling and ERK activation, Cd promoted sustained EGFR signaling to trigger Akt/mTOR cascade. The unique signaling dynamics of EGFR induced by Cd provoked responses that preferably enhanced the metastatic capacity rather than the growth. Furthermore, blockade of EGFR abrogated the promoting effects of Cd on the liver metastasis of CRC cells. In conclusion, this study provides a better understanding of the long-term influences of environmental Cd on CRC metastasis and reveals the unique EGFR signaling dynamics induced by Cd exposure.

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is activated by ligand binding, overexpression, or mutation. It is well known for its tyrosine kinase-dependent oncogenic activities in a variety of human cancers. A large number of EGFR inhibitors have been developed for cancer treatment, including monoclonal antibodies, tyrosine kinase inhibitors, and a vaccine. The EGFR inhibitors are aimed at inhibiting the activation or the activity of EGFR tyrosine kinase. However, these agents have shown efficacy in only a few types of cancers. Drug resistance, both intrinsic and acquired, is common even in cancers where the inhibitors have shown efficacy. The drug resistance mechanism is complex and not fully known. The key vulnerability of cancer cells that are resistant to EGFR inhibitors has not been identified. Nevertheless, it has been increasingly recognized in recent years that EGFR also possesses kinase-independent oncogenic functions and that these noncanonical functions may play a crucial role in cancer resistance to EGFR inhibitors. In this review, both kinase-dependent and -independent activities of EGFR are discussed. Also discussed are the mechanisms of actions and therapeutic activities of clinically used EGFR inhibitors and sustained EGFR overexpression and EGFR interaction with other receptor tyrosine kinases to counter the EGFR inhibitors. Moreover, this review discusses emerging experimental therapeutics that have shown potential for overcoming the limitation of the current EGFR inhibitors in preclinical studies. The findings underscore the importance and feasibility of targeting both kinase-dependent and -independent functions of EGFR to enhance therapeutic efficacy and minimize drug resistance. SIGNIFICANCE STATEMENT: EGFR is a major oncogenic driver and therapeutic target, but cancer resistance to current EGFR inhibitors remains a significant unmet clinical problem. This article reviews the cancer biology of EGFR as well as the mechanisms of actions and the therapeutic efficacies of current and emerging EGFR inhibitors. The findings could potentially lead to development of more effective treatments for EGFR-positive cancers.

Cell signaling by receptor protein tyrosine kinases (RTKs) is tightly controlled by the counterbalancing actions of receptor protein tyrosine phosphatases (RPTPs). Due to their role in attenuating the signal-initiating potency of RTKs, RPTPs have long been viewed as therapeutic targets. However, the development of activators of RPTPs has remained limited. We previously reported that the homodimerization of a representative member of the RPTP family (protein tyrosine phosphatase receptor J or PTPRJ) is regulated by specific transmembrane (TM) residues. Disrupting this interaction by single point mutations promotes PTPRJ access to its RTK substrates (e.g., EGFR and FLT3), reduces RTK's phosphorylation and downstream signaling, and ultimately antagonizes RTK-driven cell phenotypes. Here, we designed and tested a series of first-in-class pH-responsive TM peptide agonists of PTPRJ that are soluble in aqueous solution but insert as a helical TM domain in lipid membranes when the pH is lowered to match that of the acidic microenvironment of tumors. The most promising peptide reduced EGFR's phosphorylation and inhibited cancer cell EGFR-driven migration and proliferation, similar to the PTPRJ's TM point mutations. Developing tumor-selective and TM-targeting peptide binders of critical RPTPs could afford a potentially transformative approach to studying RPTP's selectivity mechanism without requiring less specific inhibitors and represent a novel class of therapeutics against RTK-driven cancers.

Because of long-term immunosuppression, solid organ transplant recipients are at increased risk for keratinocyte cancer. We matched solid organ transplant patients (n = 150), cases with keratinocyte cancers and tumor-free controls, considering the most important risk factors for keratinocyte cancer in solid organ transplant recipients. Using whole exome data of germline DNA from this patient cohort, we identified several genetic loci associated with the occurrence of multiple keratinocyte cancers. We found one genome-wide significant association of a common single nucleotide polymorphism located in EXOC3 (rs72698504). In addition, we found several variants with a p-value of less than 10^-5 associated with the number of keratinocyte cancers. These variants were located in the genes CYB561, WASHC1, PITRM1-AS1, MUC8, ABI3BP, and THBS2-AS1. Using whole exome sequencing data, we performed groupwise tests for rare missense variants in our dataset and found robust associations (p < 10^-6, Burden Zeggini test) between MC1R, EPHA8, EPO, MYCT1, ADGRG3, and MGME1 and keratinocyte cancer. Thus, overall, we detected genes involved in pigmentation/UV protection, tumor suppression, immunomodulation, intracellular traffic, and response to UV as genetic risk factors for multiple keratinocyte cancers in solid organ transplant recipients. We also grouped selected genes to pathways and found a selection of genes involved in the "cellular response to UV" to be significantly associated with multiple keratinocyte cancers.

Introduction: Glioblastoma (GBM) patients have a 20-30 incidence of venous thromboembolic events. EGFR is a widely used prognostic marker for many cancers. Recent lung cancer studies have described relationships between EGFR amplification and an increased incidence of thromboembolic complications. We aim to explore this relationship in glioblastoma patients. Methods: Two hundred ninety-three consecutive patients with IDH wild-type GBM were included in the analysis. The amplification status of EGFR was measured using fluorescence in situ hybridization (FISH). Centromere 7 (CEP7) expression was recorded to calculate the EGFR-to-CEP7 ratio. All data were collected retrospectively through chart review. Molecular data were obtained through the surgical pathology report at the time of biopsy. Results: There were 112 subjects who were EGFR-amplified (38.2%) and 181 who were non-amplified (61.8%). EGFR amplification status was not significantly correlated with VTE risk overall (p = 0.2001). There was no statistically significant association between VTE and EGFR status after controlling for Bevacizumab therapy (p = 0.1626). EGFR non-amplified status was associated with an increased VTE risk in subjects greater than 60 years of age (p = 0.048). Conclusions: There was no significant difference in occurrence of VTE in patients with glioblastoma, regardless of EGFR amplification status. Patients older than 60 years of age with EGFR amplification experienced a lower rate of VTE, contrary to some reports on non-small-cell lung cancer linking EGFR amplification to VTE risk.

The epidermal growth factor receptor (EGFR) plays a critical role in the tumorigenesis of various forms of cancer. Targeting the mutant forms of EGFR has been identified as an attractive therapeutic approach and led to the approval of three generations of inhibitors. The quinazoline core has emerged as a favorable scaffold for the development of novel EGFR inhibitors due to increased affinity for the active site of EGFR kinase. Currently, there are five first-generation (gefitinib, erlotinib, lapatinib, vandetanib, and icotinib) and two second-generation (afatinib and dacomitinib) quinazoline-based EGFR inhibitors approved for the treatment of various types of cancers. The aim of this review is to outline the structural modulations favorable for the inhibitory activity toward both common mutant (del19 and L858R) and resistance-conferring mutant (T790M and C797S) EGFR forms, and provide an overview of the newly synthesized quinazoline derivatives as potentially competitive, covalent or allosteric inhibitors of EGFR.

Epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, and mutated in multiple cancers. In normal cell physiology, EGFR signaling controls cellular differentiation, proliferation, growth, and survival. During tumorigenesis, mutations in EGFR lead to increased kinase activity supporting survival, uncontrolled proliferation, and migratory functions of cancer cells. Molecular agents targeting the EGFR pathway have been discovered, and their efficacy has been demonstrated in clinical trials. To date, 14 EGFR-targeted agents have been approved for cancer treatments.

This review describes the newly identified pathways in EGFR signaling, the evolution of novel EGFR-acquired and innate resistance mechanisms, mutations, and adverse side effects of EGFR signaling inhibitors. Subsequently, the latest EGFR/panEGFR inhibitors in preclinical and clinical studies have been summarized. Finally, the consequences of combining immune checkpoint inhibitors and EGFR inhibitors have also been discussed.

As new mutations are threatened against EGFR-tyrosine kinase inhibitors (TKIs), we suggest the development of new compounds targeting specific mutations without inducing new mutations. We discuss potential future research on developing EGFR-TKIs specific for exact allosteric sites to overcome acquired resistance and reduce adverse events. The rising trend of EGFR inhibitors in the pharma market and their economic impact on real-world clinical practice are discussed.

A 50-year-old woman who had previously undergone right hemicolectomy and chemotherapy for colorectal cancer was hospitalized with respiratory failure. Chest computed tomography showed reticulonodular opacities and enlarged lymph nodes. A transbronchial biopsy revealed adenocarcinoma with epidermal growth factor receptor (EGFR) mutations T790M and L861Q. Treatment with the EGFR-tyrosine kinase inhibitor (TKI) osimertinib was started, and she achieved a partial response. We diagnosed her with metastatic lung tumors from colorectal cancer based on additional immunohistochemical staining and the EGFR mutation status (L861Q) of the specimens. Although cases with EGFR mutations have been rarely reported, an EGFR-TKI can be an effective treatment option for colorectal cancer.

Colorectal cancer (CRC) is a severe health concern that results from a cocktail of genetic, epigenetic, and environmental abnormalities. Because it is the second most lethal malignancy in the world and the third-most common malignant tumor, but the treatment is unavailable. The goal of the current study was to use bioinformatics and systems biology techniques to determine the pharmacological mechanism underlying putative important genes and linked pathways in early-onset CRC. Computer-aided methods were used to uncover similar biological targets and signaling pathways associated with CRC, along with bioinformatics and network pharmacology techniques to assess the effects of enzastaurin on CRC. The KEGG and gene ontology (GO) pathway analysis revealed several significant pathways including in positive regulation of protein phosphorylation, negative regulation of the apoptotic process, nucleus, nucleoplasm, protein tyrosine kinase activity, PI3K-Akt signaling pathway, pathways in cancer, focal adhesion, HIF-1 signaling pathway, and Rap1 signaling pathway. Later, the hub protein module identified from the protein-protein interactions (PPIs) network, molecular docking and molecular dynamics simulation represented that enzastaurin showed strong binding interaction with two hub proteins including CASP3 (-8.6 kcal/mol), and MCL1 (-8.6 kcal/mol), which were strongly implicated in CRC management than other the five hub proteins. Moreover, the pharmacokinetic features of enzastaurin revealed that it is an effective therapeutic agent with minimal adverse effects. Enzastaurin may inhibit the potential biological targets that are thought to be responsible for the advancement of CRC and this study suggests a potential novel therapeutic target for CRC.

Kinase domain duplications (KDDs) have recently been recognized as oncogenic mutations and possible association with drug resistance in cancers.

Here, targeted sequencing was performed with the tumor tissue and/or plasma from 65 cancer patients with KDDs.

Intact KDDs were identified in approximately 0.1% of the total population across multiple cancer types. EGFR KDD was first identified in colorectal cancer and breast cancer, whereas FGFR2 KDD was first identified in gastric cancer. Tumors with EGFR KDD displayed lower concurrent TP53 gene alterations (p = 0.03) and slightly higher chromosome instability (p = 0.27) compared to tumors with non-EGFR-KDDs. Immune pathway analysis further revealed the enrichment of the cytokine receptors pathway (93%) in the KDD carriers. Hyperprogression-related gene mutations were identified in four cases.

Collectively, our data revealed the genomic features of KDD alterations in a multi-cancer cohort, providing more information for the potential treatment application in the KDD carriers.

Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases' functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.

Targeted degradation of cell surface and extracellular proteins via lysosomal delivery is an important means to modulate extracellular biology. However, these approaches have limitations due to lack of modularity, ease of development, restricted tissue targeting and applicability to both cell surface and extracellular proteins. We describe a lysosomal degradation strategy, termed cytokine receptor-targeting chimeras (KineTACs), that addresses these limitations. KineTACs are fully genetically encoded bispecific antibodies consisting of a cytokine arm, which binds its cognate cytokine receptor, and a target-binding arm for the protein of interest. We show that KineTACs containing the cytokine CXCL12 can use the decoy recycling receptor, CXCR7, to target a variety of target proteins to the lysosome for degradation. Additional KineTACs were designed to harness other CXCR7-targeting cytokines, CXCL11 and vMIPII, and the interleukin-2 (IL-2) receptor-targeting cytokine IL-2. Thus, KineTACs represent a general, modular, selective and simple genetically encoded strategy for inducing lysosomal delivery of extracellular and cell surface targets with broad or tissue-specific distribution.

Overexpression of deoxythymidylate kinase (DTYMK) has been associated with more aggressiveness and pathological behaviors in hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC). However, the expression of DTYMK and its prognostic significance in colorectal cancer (CRC) patients are yet unknown. The goal of this study was to investigate the DTYMK immunohistochemistry reactivity in CRC tissues and to see how it correlated with various histological and clinical features as well as survival.

Several bioinformatics databases and two tissue microarrays (TMAs) of 227 cases were used in this study. Immunohistochemistry assay was used to study the protein expression of DTYMK.

Based on the GEPIA, UALCAN, and Oncomine databases, DTYMK expression has increased in tumor tissues at both RNA and protein levels in colorectal adenocarcinoma (COAD) compared to normal tissues. A high DTYMK H-score was found in 122/227 (53%) of the cases, whereas a low DTYMK H-score was found in 105/227. The age at diagnosis (P = 0.036), stage of the disease (P = 0.038), and site of origin (P = 0.032) were all linked to a high DTYMK H-score. Patients with high level of DTYMK had bad overall survival. Interestingly, high DTYMK protein level was associated with PSM2 (P = 0.002) and MSH2 (P = 0.003), but not with MLH2 or MSH6.

This is the first study to cover the expression and prognostic significance of DTYMK in CRC. DTYMK was upregulated in CRC and could be considered as a prognostic biomarker.

A new lead compound has been designed as an antiangiogenic EGFR inhibitor that has the pharmacophoric characteristics to bind with the catalytic pocket of EGFR protein. The designed lead compound is a (para-chloro)acetamide derivative of the alkaloid, theobromine, (T-1-PCPA). At first, we started with deep density functional theory (DFT) calculations for T-1-PCPA to confirm and optimize its 3D structure. Additionally, the DFT studies identified the electrostatic potential, global reactive indices and total density of states expecting a high level of reactivity for T-1-PCPA. Secondly, the affinity of T-1-PCPA to bind and inhibit the EGFR protein was studied and confirmed through detailed structure-based computational studies including the molecular docking against EGFR^WT and EGFR^T790M, Molecular dynamics (MD) over 100 ns, MM-GPSA and PLIP experiments. Before the preparation, the computational ADME and toxicity profiles of T-1-PCPA have been investigated and its safety and the general drug-likeness predicted. Accordingly, T-1-PCPA was semi-synthesized to scrutinize the proposed design and the obtained in silico results. Interestingly, T-1-PCPA inhibited in vitro EGFR^WT with an IC₅₀ value of 25.35 nM, comparing that of erlotinib (5.90 nM). Additionally, T-1-PCPA inhibited the growth of A549 and HCT-116 malignant cell lines with IC₅₀ values of 31.74 and 20.40 µM, respectively, comparing erlotinib that expressed IC₅₀ values of 6.73 and 16.35 µM, respectively.

A new semisynthetic derivative of the natural alkaloid, theobromine, has been designed as a lead antiangiogenic compound targeting the EGFR protein. The designed compound is an (m-tolyl)acetamide theobromine derivative, (T-1-MTA). Molecular Docking studies have shown a great potential for T-1-MTA to bind to EGFR. MD studies (100 ns) verified the proposed binding. By MM-GBSA analysis, the exact binding with optimal energy of T-1-MTA was also identified. Then, DFT calculations were performed to identify the stability, reactivity, electrostatic potential, and total electron density of T-1-MTA. Furthermore, ADMET analysis indicated the T-1-MTA's general likeness and safety. Accordingly, T-1-MTA has been synthesized to be examined in vitro. Intriguingly, T-1-MTA inhibited the EGFR protein with an IC50 value of 22.89 nM and demonstrated cytotoxic activities against the two cancer cell lines, A549, and HCT-116, with IC50 values of 22.49, and 24.97 μM, respectively. Interestingly, T-1-MTA's IC50 against the normal cell lines, WI-38, was very high (55.14 μM) indicating high selectivity degrees of 2.4 and 2.2, respectively. Furthermore, the flow cytometry analysis of A549 treated with T-1-MTA showed significantly increased ratios of early apoptosis (from 0.07% to 21.24%) as well as late apoptosis (from 0.73% to 37.97%).

Colon cancer is the world's fourth leading cause of death. It is cancer of the latter part of the large intestine, i.e. the colon. Chronic inflammation over a long period also leads to the development of cancer. Cancer in the colon region is arduous to diagnose and is detected at a later stage when it metastasizes to other parts of the body like the liver, lungs, peritoneum, etc. Colon cancer is a great example of solid tumours associated with chronic inflammation. Although conventional therapies are effective, they lose their effectiveness beyond a certain point. Relapse of the disease occurs frequently. RNA interference (RNAi) is emerging as a great tool to specifically attack the cancer cells of a target site like the colon. RNAi deals with epigenetic changes made in the defective cells which ultimately leads to their death without harming the healthy cells. In this review, two types of epigenetic modulators have been considered, namely siRNA and miRNA, and their effect on interleukins. Interleukins, a class of cytokines, are major inflammatory responses of the body that are released by immune cells like leukocytes and macrophages. Some of these interleukins are pro-inflammatory, thereby promoting inflammation which eventually causes cancer. RNAi can prevent colon cancer by inhibiting pro-inflammatory interleukins.

Colorectal cancer (CRC) is among the most commonly diagnosed gastrointestinal malignancies worldwide. It is inadequate to handle in terms of staging and restaging only based on morphological imaging modalities and serum surrogate markers. And the correct and timely staging of CRC is imperative to prognosis and management. When compared to established sequential, multimodal conventional diagnostic methods, the molecular and functional imaging ¹⁸F-FDG PET/CT shows superiorities for tailoring appropriate treatment maneuvers to each patient. This review aims to summarize the utilities of ¹⁸F-FDG PET/CT in CRC, focusing on primary staging, follow-up assessment of tumor responses and diagnostic of recurrence. In addition, we also summarize the technical considerations of PET/CT and the conventional imaging modalities in those patients who are either newly diagnosed with CRC or has already been treated from this cancer.