Clinical Overview: Adjunctive Role of Metformin in Enhancing Paclitaxel’s Therapeutic Actions in Endometrial Cancer

Endometrial cancer often begins as a benign lump in the uterine lining but can spread to other organs as a malignant tumor. It is closely associated with obesity, polycystic ovary syndrome (PCOS), and diabetes.¹

Endometrial cancer is treated based on severity with surgery, radiation, or chemotherapy medications, such as cisplatin, carboplatin, or paclitaxel. Metformin is used as a first-line therapy to target risk factors that contribute to endometrial cancer, such as PCOS and obesity.

Specifically, it works by regulating blood sugar levels, decreasing androgen levels, and allowing weight loss. Other treatment options include surgical removal of the fallopian tubes, radiation therapy via X-rays, or immunotherapy.

Paclitaxel is an antimicrotubule agent that inhibits cell replication,² whereas carboplatin is an alkylating agent that inhibits DNA synthesis.³ Although paclitaxel is FDA-approved for breast cancer and carboplatin is approved for ovarian cancer, they are used as a conjunctive therapy for endometrial cancer. When used together, they increase double response rate and improve disease-free survival.

Metformin is a biguanide diabetic medication that activates AMPK and regulates mTOR downstream, a pathway that typically allows further cell proliferation. However, both medications individually may cause bone marrow suppression, so using a combination regimen can lead to additive effects and further reduce a patient’s leukocyte or thrombocyte count.

The pathway notoriously known for spreading cancer is the PI3K/AKT/mTOR signaling pathway. It is activated by cellular stress, especially during times of insulin resistance. In diabetic and PCOS patients, regulating insulin levels can decrease the likelihood of malignant cancer formation.⁴

In fact, excessive mTORC1 upregulation and mTORC2 inhibition exacerbate insulin resistance and cancer growth. In terms of cancerous growth patterns, mTORC1 allows cancerous cells to remain alive whereas mTORC2 allows them to proliferate through direct phosphorylation of insulin-like growth factor.⁴

To combat elevated glucose levels in diabetic patients, the activation of mTORC1 serves to increase uptake of glucose, but excess activation can cause cells to become desensitized to insulin. Metformin particularly targets this pathway by, “[enhancing] signaling through the insulin receptor…followed by a reduction in circulating insulin levels.”⁵

This medication also reduces insulin resistance by activating AMPK phosphorylation, which intrinsically blocks mTORC1 effects. mTORC2 allows the activation of the AKT pathway to prevent glucose uptake, especially in adipose tissue, thereby expediting the developing diabetes and obesity.

In recent studies, combination therapy of metformin and low-dose paclitaxel produced similar tumor regression results as using paclitaxel as a sole therapy did. Together, they synergistically inhibit the G2 DNA replication phase of cellular replication.

However, further investigation regarding their actions on S6 ribosomal protein phosphorylation is necessary, because paclitaxel allows subsequent protein and cell synthesis whereas metformin inhibits it via mTOR pathway regulation.⁵

In terms of its anti-tumorigenic activity, metformin prevents hTERT mRNA activity by inhibiting excessive telomerase expression in the endometrium. Studies hypothesize that metformin can be used to prevent the exacerbation of not only diabetes and obesity, but also for endometrium-related cancers.

The current phase 2/3 clinical trial investigating the validity of this combination therapy shows promising results. The progression-free survival rate was higher and overall survival rate was nearly 5% higher with metformin. With metformin, adverse effects (AEs) affected fewer than 20% of patients, whereas the use of the typical regimen had higher rates of thromboembolic events.⁶

Metformin improves blood glucose regulation and allows weight loss, thereby decreasing the likelihood of developing endometrial cancer. However, there is not enough safety and efficacy information published regarding mTOR inhibitors and the use of metformin for treating endometrial cancer. Further research is needed to determine which AEs may arise with use of metformin as an adjunctive therapy with paclitaxel and carboplatin.

References

1. Endometrial Cancer. John Hopkins Medicine. Available at: https://www.hopkinsmedicine.org/health/conditions-and-diseases/endometrial-cancer.
2. Abraxane (Paclitaxel) Label. Food and Drug Administration. 2020: 3-9. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021660s047lbl.pdf.
3. Paraplatin (Carboplatin) Label. Food and Drug Administration. 2010: 6-9. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020452s005lbl.pdf.
4. Shi Ong P, Wang L, Dai X, et al. Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives. Frontiers in Pharmacology. 2016 Oct 25; 7: 395. doi:10.3389/fphar.2016.00395.
5. Hanna RK, Zhou C, Malloy KM, et al. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecol Oncol. 2012 May;125(2):458-69. doi: 10.1016/j.ygyno.2012.01.009.
6. Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer. ClinicalTrials.gov. 2021 September. Available at: https://clinicaltrials.gov/ct2/show/results/NCT02065687?view=results