Life Sciences & Biotechnology
Title : | Exploiting the fitness cost of transforming growth factor-b signaling pathway-dependency of chemotherapy-resistant, senescent triple negative breast cancer cells: An evolution-guided therapeutic approach |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Cancer Biology and Therapeutics |
Principal Investigator : | Dr. Anindita Chakrabarty, Shiv Nadar Institution Of Eminence, Uttar Pradesh |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | anindita.ac@gmail.com |
Details
Executive Summary : | Combination chemotherapies are the standard-of-care for triple negative breast cancer (TNBC) patients. Newly-diagnosed TNBCs are usually more sensitive to chemotherapies. However, patients who don’t achieve complete pathological response in the first-line regimen, develop resistance in the second, third and fourth-line settings. According to the principles of evolutionary biology, this is inevitable because chemotherapies, when administered at the maximum-tolerated doses, result in competitive release of rare drug-resistant clones. Tumor heterogeneity is one of the major culprits of such clonal evolution. Among diverse molecular mechanisms of chemoresistance, induction of a reversible growth-arrested senescent (therapy-induced senescence/TIS) state plays a central role in the establishment and maintenance of the resistant phenotype, ultimately resulting in tumor relapse, metastasis and reduced patient survival. Because, induction of TIS is a common occurrence in both experimental and clinical settings in many cancer types including TNBC, we speculated this to be an evolutionary preferred mode for selection and release of resistant clones. One of the evolution-directed/adaptive therapeutic strategies allows exploitation of the fitness cost of resistance; in this scenario, it is the drug-induced senescent population. This has been thoroughly tested and found to be successful in delaying proliferation of multidrug-resistant phenotypes and increasing the progression-free survival in breast cancer. While searching for an appropriate fitness cost of senescent population following chemotherapy treatment, we came across autocrine secretion of transforming growth factor-b (TGF-b) and activation of the signaling pathway. A pleiotropic cytokine with both tumor-suppressive and oncogenic functions, TGF-b also plays central roles in senescence, aging, aging-related pathologies, chemotherapy-resistance and metastasis. There have been several attempts to utilize TGF-b pathway inhibitors as combination therapies to prevent chemoresistance in TNBC. However, the results obtained so far are variable, arguing that a better approach is warranted to take advantage of TGF-b addiction for enhancing chemotherapy efficacy. Because of the central role of the TGF-b signaling in both senescence and drug resistance, we hypothesize that the dependency on this pathway is a fitness cost for both chemoresistant and therapy-induced senescent populations and interfering with such cost in TNBC will enable us to delay/prevent evolution of TIS and subsequent expansion of resistant clones. We expect this evolution-guided strategy to be less toxic and more effective than the conventional dose-dense therapeutic modalities. |
Total Budget (INR): | 59,03,786 |
Organizations involved