Projects

Abstract: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer and is defined by neuroendocrine features, high rate of metastasis, and strong association with smoking. SCLC patient respond to chemotherapy at first, however, relapse quickly with acquired resistance to other chemotherapies. Even the immune checkpoint inhibitors have shown only marginal benefits in SCLC patients. Therefore, there is an utmost need to develop novel therapeutic agents against this deadly subtype of lung cancer. Screening of patient samples has identified mutation in REaranged during Transfection (RET) gene linked to SCLC pathogenesis. However, its clinical significance in SCLC has not been studied yet. Here, we are analyzing the ability of Pralsetinib, a highly potent and selective inhibitor of RET, to inhibit SCLC in pre-clinical mouse models of SCLC. RET signaling in monocytes has been shown to increase the expression of chemokine and cytokines associated with myeloid-derived suppressor cells (MDSCs). Tumors are known to recruit MDSCs to inhibit anti-tumor immune response and dampen immunotherapy response. We will also analyze the ability of Pralsetinib to activate anti-tumor immune responses and enhance the efficacy of immunotherapy against SCLC by suppressing MDSCs. Overall, these studies will help in establishing the preclinical significance of Pralsetinib against SCLC progression and clinical response to immunotherapy.

Abstract: Although SCLC patients respond to initial chemotherapies, most of them will inevitably relapse, resulting in early death. High incidence of metastasis and drug resistance are the major factors responsible for reduced survival observed in SCLC patients compared to other type of lung cancers. Therefore, there is a significant need to develop novel therapeutic agents against SCLC. I this regard, we are analyzing the therapeutic utility of Umbralisib in transgenic and patient-derived xenograft mouse models of SCLC. Umbralisib is a dual Phosphatidylinositol-3-kinase δ (PI3Kδ) and casein kinase-1ε (CK1ε) inhibitor. PI3Kδ and CK1ε are dysregulated in SCLC and are known to drive translation of various oncogenes, including MYC, which is involved in SCLC progression and drug resistance. We hypothesize that a clinically approved Umbralisib may inhibit SCLC progressing and metastasis by suppressing various oncogenic activities. In this proposal, we will evaluate the ability of Umbralisib to prevent or delay the malignant transformation of the lungs and subsequent progression/metastasis in a transgenic and patient derived-xenograft mouse model of SCLC. We will further analyze if Umbralisib can inhibit MYC signaling and act synergistically with chemotherapy against aggressive and metastatic SCLC. These studies will establish the therapeutic potential of Umbralisib against SCLC progression, metastasis and drug resistance.

Title: Development of novel metabolic inhibitors against small cell lung cancer

Funding agency: Science and Engineering Research Board

Scheme: Start-up Research Grant

Duration: 2023-2026

Amount: 30 lakh