Metabolic axis of autophagy: A key player in tumor maintenance and opportunities for therapeutic exploitation

Table 1 List of preclinical/clinical studies on use of autophagy inhibitors as monotherapeutic agent and their mechanism of action in human cancer types

Cancer type(s)	Pre-clinical/clinical phase	Trial identifier
Melanoma (stage III/IV)	0 (pilot study)	NCT00962845
Renal cell carcinoma	I	NCT01144169
Chronic lymphocytic leukemia	II	NCT00771056
Metastatic pancreatic adenocarcinoma	II	NCT01273805
Breast ductal carcinoma in situ	I/II	NCT01023477
Brain metastases with whole brain radiation therapy	II	NCT01894633
DCC-3116 (ULK1 inhibitor): Targets ULK1 and blocks early autophagy initiation
Kras-mutated or Raf-mutated advanced solid tumors	I (first in human)	NCT04892017
SBI-0206965 (ULK1 inhibitor): Targets ULK1 kinase and inhibits early phase autophagy initiation
Non-small cell lung cancer cells, neuroblastoma	Preclinical studies on cell lines and mouse models	Not available
Verteporfin (photoactivatable autophagy inhibitor): Inhibits autophagosome formation and lysosomal degradation
Glioblastoma, pancreatic ductal adenocarcinomas	I/II	NCT03033225
3-Methyladenine: Targets class III phosphatidylinositol 3-kinase (vacuolar protein sorting 34), thereby blocks autophagosome formation (early-stage autophagy)
Cervical cancer, breast cancer, glioblastoma, hepatocellular carcinoma, colon cancer, ovarian cancer, pancreatic cancer, leukemia, mantle cell lymphoma	Preclinical studies on cell lines and murine models	Not available
Lys05 (lysosome deacidifier): Late-stage autophagy inhibitor
Glioblastoma, colorectal cancer, melanoma, acute myeloid leukemia	Preclinical studies on cell lines and murine models	Not available

ULK: Unc-51 like autophagy activating kinase.

Table 2 List of preclinical/clinical studies on autophagy modulation followed by application of anticancer drug and their key endpoints in human cancer

Cancer types	Autophagic inducer	Anticancer therapy	Clinical phase	Key endpoints	Trial identifier
Advanced solid/hematologic malignancies	FMD repeated every 3-4 weeks, up to a maximum of eight cycles	Carboplatin-based chemotherapy, pembrolizumab, abraxane-gemcitabine, and XELIRI-bevacizumab	I/II	Safe and feasible; enhanced systemic and intratumor antitumor immunity; exceptional tumor responses in approximately 5 patients in sub-analysis	NCT03340935
HER2-negative breast cancer	STF (approximately 24 hours before and after chemo)	Docetaxel/doxorubicin/cyclophosphamide	II/III	Reduced hematologic toxicity and DNA damage in peripheral blood mononuclear cells vs non-fasting	NCT01304251
Breast and ovarian cancer	STF (36 hours before, 24 hours after chemo; total approximately 60 hours)	Adjuvant chemotherapy	III	Better quality of life and reduced fatigue during chemo cycles with fasting; no serious adverse effects	NCT01954836
HER2-negative stage II/III breast cancer	Cyclic FMD (3 days prior + during chemo) vs standard diet	Anthracycline-taxane	II/III	Radiological and pathological responses (miller and payne 4/5) more frequent with FMD; reduced DNA damage in T-lymphocytes; toxicity not significantly different despite no dexamethasone in FMD	NCT02126449
Solid and hematologic malignancies	Cyclic 5-day FMD administered every approximately 3 weeks; supplemented with nutritional and muscle training during refeeding	Chemotherapy, endocrine, targeted, checkpoint inhibitors, radiotherapy	I/II single arm	Lower IGF-1, leptin; better body composition; feasible	NCT03595540
Stage I-III triple negative breast cancer	Eight triweekly cycles of 5-day FMD	Metformin with standard preperative anthracycline-taxane chemotherapy	II	The pCR rate; plasma glucose, insulin, IGF-1, lipid and amino acid shifts; radiologic response, distant metastasis free survival, recurrence free survival, overall survival up to 5 years; adverse effects incidence/severity, adherence to regimen, dosage modifications; tumor/metabolic gene expression; association with pCR; biomarker discovery	NCT04248998
Gynecologic cancers (breast and ovarian cancer)	Intermittent fasting of 72-84 hours parallel to the application of the chemotherapy	Breast cancer: Epirubicin + cyclophosphamide + paclitaxel and doxorubicin + cyclophosphamide + docetaxel. Ovarian cancer: Paclitaxel + carboplatin	Not assigned	Lowered fatigue and improved quality of life. Evaluated chemotherapy side effects, tumor response, metabolic changes (e.g., weight, glucose, insulin), and long-term outcomes including recurrence and biomarker trends	NCT03162289
Advanced metastatic prostate cancer	60 hours fasting-mimicking diet (36 hours before + 24 hours after chemo)	Docetaxel in some cases; abiraterone (combined with prednisone)	Not assigned	Quality-of-life at 3 months and 6 months, hospital anxiety and depression scale score changes, blood counts, chemo side-effects	NCT02710721
Metastatic non-small cell lung cancer	FMD 3 days prior	Carboplatin + pemetrexed + pembrolizumab	II	Patients did not experience serious adverse events; DNA damage in blood cells; circulating tumor cell spheroid formation; changes in immune biomarkers	NCT03700437
Metastatic castratesensitive prostate adenocarcinoma	FMD 5 days/month for 6 months	Abiraterone, apalutamide, enzalutamide, or darolutamide	II	Metabolic outcomes, including weight, blood glucose, insulin levels; biomarkers of treatment response, such as changes in prostate-specific antigen and inflammatory markers	NCT05832086
Lung cancer	FMD	Cisplatin, carboplatin, and agents like pemetrexed, alongside metformin	II	Progression-free survival; feasibility and safety of the FMD + metformin combination; immune and metabolic biomarker changes (e.g., peripheral blood mononuclear cells, DNA damage markers, metabolic health); overall response rate and tolerability of adjunctive interventions	NCT03709147

FMD: Fasting mimicking diets; HER2: Human epidermal growth factor receptor 2; IGF1: Insulin-like growth factor 1; pCR: Pathologic complete response; STF: Short-term fasting.