Combinatorial treatment of diffuse large B cell lymphoma with Metformin and novel therapeutic candidates

PhD student: Lejla Mahmutovic

Mentor: Assist. Prof. Dr. Mirza Suljagic

The most common problem in the therapy of many hematological malignancies is the generation of resistance to current treatment options. Combined therapy using molecules with low toxicity and aiming for multiple pro-survival targets in cancer cells can be used in order to overcome this problem. Repurposing of compounds already used in therapy and usage of natural molecules is highly desirable. Metformin, the most prescribed oral anti-diabetic drug in the world, is now extensively evaluated as an anti-cancer agent. Numerous studies have shown that metformin decreases cancer risk in diabetic patients (1,2) and has led to a large number of clinical trials utilizing anticancer effects of metformin as monotherapy or in combination with different agents in non-diabetic patients (3). Moreover, recent findings have suggested the role of metformin in the treatment of diffuse large B-cell lymphoma (DLBCL) (4–6) an aggressive type, representing 30–40% of all non-Hodgkin lymphomas (NHL) (7,8).

Since DLBCL shows clinical, pathological and molecular heterogeneities, it is assumed that approximately 30% to 40% of DLBCL patients do not respond well to common therapy regimens (7). The most common treatment, where approximately more than half of the patients can be cured, includes the standard immunochemotherapy regimen rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone R-CHOP (7,8). However, approximately 30% of patients are not being cured, and DLBCL remains a noteworthy clinical challenge (9).

Great effort has been done to develop new therapeutic approaches for these refractory or relapsed patients, with some significant success. To define potential therapeutic targets and develop regimens for the treatment of DLBCL, it is crucial to understand the pathogenesis of DLBCL (7,8,10). As in other cancer types, dysregulation of cell survival or resistance to cell death also affects the pathogenesis of DLBCL. It is reported that DLBCL has evolved many strategies to resist cell death, which potentially can be therapeutically targeted (8).

KEY OBJECTIVES

One of the key objectives of the project is the identification of the targets involved in the main signaling pathways and anticancer effects after metformin and currently used therapeutics and novel anti-lymphoma drugs mono-therapy and in combination.

It was found that human leukemic and breast cancer cells with increased basal Akt phosphorylation were shown to be resistant to metformin-induced apoptosis (11,12) and that metformin anticancer effects can be enhanced by combination with Akt inhibitors (11).

The role of the NF-κB pathway in single and combinatorial therapy with metformin will be evaluated. It was shown that the NF-κB pathway controls the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition increases the sensitivity of tumor cells to metabolic challenges such as inhibition of mitochondrial complex I caused by metformin. As a result, a combination of NF-κB inhibitors and metformin diminishes tumorigenesis in vivo (13). For this reason, we aim to explain whether metformin and novel therapeutic agents are able to inhibit proliferation and induce apoptosis in lymphoma cells.

References

  1. Pierotti MA, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T, et al. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene. 2013 Mar 21;32(12):1475–87.
  2. Christodoulou M-I, Scorilas A. Metformin and anti-cancer therapeutics: hopes for a more enhanced armamentarium against human neoplasias? Curr Med Chem. 2016 Sep 7;
  3. Rosilio C, Ben-Sahra I, Bost F, Peyron J-F. Metformin: a metabolic disruptor and anti-diabetic drug to target human leukemia. Cancer Lett. 2014 May 1;346(2):188–96.
  4. Chukkapalli V, Gordon LI, Venugopal P, Borgia JA, Karmali R. Metabolic changes associated with metformin potentiates Bcl-2 inhibitor, Venetoclax, and CDK9 inhibitor, BAY1143572 and reduces viability of lymphoma cells. Oncotarget. 2018 Apr 20
  5. Xuan Koo Y, Tan DSW, Tan IBH, Tai DWM, Ha T, Sze Ong W, et al. Effect of concomitant statin, metformin, or aspirin on rituximab treatment for diffuse large B-cell lymphoma. Leuk Lymphoma. 2011 Aug;52(8):1509–16.
  6. Alkhatib Y, Abdel Rahman Z, Kuriakose P. Clinical impact of metformin in diabetic diffuse large B-cell lymphoma patients: a case-control study. Leuk Lymphoma. 2017 May 4;58(5):1130–4.
  7. Hershkovitz-Rokah O, Geva P, Salmon-Divon M, Shpilberg O, Liberman-Aronov S. Network analysis of microRNAs, genes and their regulation in diffuse and follicular B-cell lymphomas. Oncotarget. 2018 Jan 30
  8. Miao Y, Medeiros LJ, Xu-Monette ZY, Li J, Young KH. Dysregulation of Cell Survival in Diffuse Large B Cell Lymphoma: Mechanisms and Therapeutic Targets. Front Oncol. 2019 Mar 1
  9. He Y, Li J, Ding N, Wang X, Deng L, Xie Y, et al. Combination of Enzastaurin and Ibrutinib synergistically induces anti-tumor effects in diffuse large B cell lymphoma. J ExpClin Cancer Res. 2019 Dec
  10. Mondello P, Mian M. Front‐line treatment of Diffuse large B‐cell lymphoma: beyond R‐CHOP. Hematol Oncol. 2019 Apr 2
  11. Scotland S, Saland E, Skuli N, de Toni F, Boutzen H, Micklow E, et al. Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells. Leukemia. 2013 Nov;27(11):2129–38.
  12. Scherbakov AM, Sorokin DV, Tatarskiy VV, Prokhorov NS, Semina SE, Berstein LM, et al. The phenomenon of acquired resistance to metformin in breast cancer cells: The interaction of growth pathways and estrogen receptor signaling. IUBMB Life. 2016 Apr;68(4):281–92.
  13. Mauro C, Leow SC, Anso E, Rocha S, Thotakura AK, Tornatore L, et al. NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat Cell Biol. 2011 Oct;13(10):1272–9.