Biology subjects

Desai, B.

Publications and source records attributed to Desai, B..

3 recordsLinked to original sources

bioRxiv2020

Anti-tumor effects of an Id antagonist with no acquired resistance

Id proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. Id proteins inhibit basic HLH transcription factors through protein-protein interactions, often inhibiting differentiation and sustaining proliferation. We recently identified a small-molecule, AGX51, which targets Id proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impaired cell growth and viability that results from a dramatic increase in ROS production upon Id degradation. In mouse models, AGX51 treatment suppressed breast cancer colonization in the lung, regressed the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduced tumor burden in a model of sporadic colorectal neoplasia. Furthermore, in cells and mice, we failed to observe acquired resistance to AGX51 likely the result of the immutability of the binding pocket and efficient degradation of the Id proteins. Thus, AGX51 is a first-in-class compound that antagonizes Id proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.

cancer biology↗

bioRxiv2019

The Pipeline for Digital Analysis of IHC Images from NSCLC Xenograft Tissues

Multiple small molecule inhibitors and immunotherapy advances have shown success by prolonging patients survival in NSCLC but patient with metastasis or advanced stage of cancer often experiences relapse. Cancer associated fibroblast (CAFs), a major cellular component of tumor microenvironment plays key role in shaping solid tumors. In-vitro studies have reported that CAFs can blunt the effect of targeted therapies in tumor cells. The current study focuses on evaluating the impact of stromal protection by analyzing immunohistochemistry (IHC) images from xenograft experiment. The study investigates if the HGF-driven CAF mediated stromal protection in cancer cell contributes to the development of resistance to Alectinib. We utilized QuPath, a digital software to automatize the readout of proliferation rate of tumor cells and evaluate the impact of stromal protection.

cancer biology↗

bioRxiv2018

Resistance to ALK targeting therapies as a gradual Darwinian adaptation to inhibitor specific selective pressures

Despite high initial efficacy, therapies that target oncogenic kinases eventually fail in advanced, metastatic cancers. This failure in initially responsive tumors is the direct result of the evolution of drug resistance under therapy-imposed selective pressures. In contrast to the massive body of experimental research on the molecular mechanisms of resistance, understanding of its evolutionary origins and dynamics remains fragmented. Using a combination of experimental studies and mathematical modeling, we sought to dissect the evolution of resistance to different clinical ALK inhibitors in an experimental model of ALK positive NSCLC. We found that resistance can originate from heterogeneous, weakly resistant, sub-populations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence of a hybrid scenario, of gradual, multifactorial development through acquisition of multiple cooperating genetic and epigenetic adaptive changes, amplified by selection. Additionally, we found that intermediate resistance phenotypes might present unique, temporally restricted collateral sensitivities, absent in therapy naive or fully resistant cells, suggesting new opportunities for therapeutic interference.

cancer biology↗