The mechanism and application of biguanide drugs in cancer treatment

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The mechanism and application of biguanide drugs in cancer treatment

The mechanism and application of biguanide drugs in cancer treatment.  Biguanides are a class of anti-diabetic drugs, including phenformin and metformin; however, the former has been withdrawn from approval by many countries due to its toxicity.

The results of retrospective epidemiological studies in diabetic populations and preclinical laboratory models show that biguanides have anti-tumor activity, indicating that they can be reused for cancer prevention and treatment.

However, there is a need to better understand how these biguanides act as anti-tumor drugs to guide their application in cancer treatment, so as to stimulate people’s interest in their pharmacology.

This study provides evidence of the mechanism of action related to metformin and its anti-tumor activity, including their effects on central carbon metabolism and immunomodulatory activity in cancer cells.

While analyzing the molecular mechanism of biguanide drugs in the treatment of cancer, this study systematically sorted out the clinical research of biguanide drugs combined with molecular targeted drugs in the treatment of tumors (see the original text for the full version).

The clinical study of biguanide combined with immunotherapy for cancer.

Mitochondrial complex I, AMPK, mTOR and mGPD are all considered to be molecular targets that mediate the anti-tumor activity of biguanides. Consistent with Complex I as the main target, biguanides preferentially target the slower-growing subgroups of cancer cells, which are more dependent on OXPHOS for survival, creating treatments for the combined application of biguanides and drugs that act on fast-circulating populations Opportunity to play a greater role in tumor clearance.

Targeting the compensatory metabolic pathways that cancer cells need to survive metabolic disorders may also improve the efficacy of biguanide combination therapy. In addition, biguanide drugs have an impact on TIME, which may affect the immune recognition and elimination of tumors. Interestingly, biguanides can also affect the pathophysiological characteristics of the host by regulating the intestinal microbiota, increasing the possibility that biguanides may indirectly affect the patient’s response to cancer treatment.

It is not clear whether biguanides affect the direct targets of cancer cells, tumor microenvironment, or symbiotic microbiota. Finally, the pharmacodynamic properties of benzformin suggest that its application in cancer treatment may be superior to metformin, because metformin has shown limited efficacy in recent clinical trials, possibly due to its more limited pharmacodynamic properties.

Although the toxicity profile of benzformin as a long-term maintenance treatment for patients with type 2 diabetes is not ideal, it can be considered for the treatment of cancer. Combining preclinical and clinical studies of biguanides, including new derivatives, will help clarify biomarkers that predict therapeutic effects, identify suitable patient groups that are sensitive to biguanides, and guide the development of cancer monotherapy and combination therapy Clinical Trials.

Using metformin may reduce the risk of basal cell carcinoma

Metformin has anti-cancer properties and is known to inhibit the sonic hedgehog pathway, but population-based studies are needed to analyze its potential protection against basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).

The study analyzed all 6880 first-time BCC, SCCis, or invasive SCC patients and 69,620 population controls diagnosed in Iceland from 2003 to 2017, and described the relationship between metformin use and invasive SCC, in situ SCC (SCCis) and BCC. The relationship between.

Even at low doses, metformin was associated with a lower risk of BCC (OR = 0.71; 95% CI: 0.61-0.83). No increase in the risk of SCC has been observed. The risk of SCCis is slightly increased in the 501-1500 daily dose unit category (OR = 1.40; 95% CI: 1.00-1.96). This study is retrospective in nature and cannot be adjusted for UV exposure, Fitzpatrick skin type, and comorbidities, and has limitations.

Metformin may have the potential as a chemoprotectant for high-risk BCC patients, which needs to be further verified in future studies.

Adalsteinsson JA, Muzumdar S, Waldman R, et al. Metformin is associated with decreased risk of basal cell carcinoma: A whole-population case-control study from Iceland. J Am Acad Dermatol. 2021 Jul;85(1):56-61 . doi: 10.1016/j.jaad.2021.02.042.

Other news: 

FDA designates VS-6766 + Defactinib as a breakthrough therapy for ovarian cancer patients

The FDA recently granted breakthrough therapy designation (BTD) to VS-6766 (a RAF/MEK inhibitor) and defactinib (a FAK inhibitor) for the treatment of patients with ovarian cancer.

Recurrent low-grade serous ovarian cancer (LGSOC) is a rare cancer subtype, accounting for 6% to 8% of all ovarian cancers, with a median survival time of about 10 years, and poor response to chemotherapy and standard treatments for ovarian cancer , Most patients will have disease recurrence. Limitations of LGSOC treatment options include low response rates and toxicity, which makes it difficult for patients to receive treatment long enough to see potential responses.

Early findings from the FRAME study of VS-6766 and defactinib showed very promising results in the treatment of patients with relapsed LGSOC. This study helped the FDA decide to grant BTD for this program.

In the most recent cohort (n = 24), the overall response rate (ORR) was 52%, the KRAS mutant ORR was 70%, the KRAS wild-type ORR was 44%, and the KRAS status undetermined ORR was 0%. In terms of side effects, the most common severity is Grade 1 or 2, including skin rash, elevated creatine kinase, nausea, hyperbilirubinemia, and diarrhea.

For LGSOC patients, the breakthrough therapy designation granted by the FDA to VS-6766 and defactinib will bring higher benefits to patients.

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