Cancer remains one of the most problematic challenges in the modern medical field. Protein kinase C (PKC) is a key regulatory enzyme that drives cell growth, division, and proliferation; although its mutation develops and progresses the growth of numerous cancers, making it a promising candidate for activity inhibition. This project focused on the synthesis of novel ligands as PKC inhibitors. The computational binding interactions of the ligands with PKC were studied. Several ligands were successfully synthesized confirmed by using spectroscopic analysis. Compounds with hydrogen bond donor and acceptor substituents at both termini exhibited high potential for PKC inhibitory activity.

As one of the leading causes of death worldwide, cancer faces several therapeutic hurdles. Chemotherapy is one of the more popular treatment methods, but its potency is often diminished by the development of multidrug resistance (MDR) in cancer cells. MDR is a multifaceted issue that involves the intertwined interaction of several molecular pathways and is still not well understood. One such pathway involves ATP-binding cassette (ABC) transporters, which are efflux pump proteins that remove chemicals from the cytosol. Efflux pump P-glycoprotein (P-gp) is one of the more researched contributors to MDR, but it falls short as a target due to poor specificity. Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) serves as a potential alternative target for novel therapeutics to overcome MDR. Compared to P-gp, ROR1 is highlighted as a superior target due to its expression in primarily cancer cells as well as the role it plays in several drug resistance pathways. Current therapeutic strategies to reverse MDR through ROR1 inhibition are also summarized and evaluated. This review describes the molecular mechanisms that make the cure to cancer so elusive, provides background on the shortcomings of modern chemotherapeutics, compares P-gp and ROR1 as targets for combating MDR, and provides context for current development of treatment approaches that target ROR1.

RELATED ABSTRACTS

• Targeting Lipid Peroxidation to Trigger Ferroptotic Cell Death in Cancer Cells, Khandhar, Pari Samir, UMass Amherst, Poster Session 3, 1:15 PM - 2:00 PM, Auditorium, A47
• Assessing Disinfection Byproduct (DBP) Formation During the Electrochemical Degradation of Per- and Polyfluoroalkyl Substances (PFAS), Colavito, Annabella, UMass Amherst, Poster Session 5, 3:15 PM - 4:00 PM, 163, C29

Targeted protein degraders have unique advantages over traditional occupancy-based inhibitors. Among these, a PROTAC-based protein degradation approach has been identified as one of the most promising pathways to combat drug resistance in cancer therapy. While the high potency of PROTACs offers clear advantages, that same feature also presents dose-limiting toxicity in other tissues. Additionally, their bivalent features and the associated high molecular weight limit the bioavailability of PROTACs. Although antibody drug conjugates (ADCs) have emerged as a potential solution for targeted delivery of therapeutics, the inherent challenges of low drug to antibody ratio (DAR) and complex synthetic requirements are yet to be overcome. Polymers provide distinct advantages over small linker molecules as they can significantly change their physical attributes upon minutely altering their chemical structures. Moreover, they can overcome the challenge of low DAR by incorporating multiple drug copies. By utilizing rational polymer design, we have developed robust antibody-nanogel conjugates which can covalently/non-covalently carry a wide variety of drug molecules. Further, we introduce chemical triggers to the polymer structure for ensuring efficient release of the therapeutics inside cells, as well as antibody-based targeting for achieving tissue specificity. Altogether, we are able to generate a universal platform for efficient delivery of PROTACs in a cell-specific manner, thereby mitigating toxicity. We envision this work to provide a generalizable platform towards a broader range of various disease models and an opportunity to harness full potential of the PROTAC technology.  

Prostate cancer (PCa) has a high propensity to metastasize to bone, leading to poor prognosis. Additionally, bone lesions from metastatic PCa appear radiologically with areas of excessive matrix formation as well as resorption. Hijacked bone-resorbing osteoclasts may be responsible for creating a dysregulated bone tissue microenvironment with variable morphological presentations. This study investigates the effects of cell-to-cell interaction between different PCa cells, each generate distinct types of metastatic bone lesions, human monocyte-derived osteoclasts precursors on osteoclast formation, activation, and subsequent bone resorption. It is hypothesized that human PC-3 PCa cells will show a higher level of influence on osteoclast formation and activation than human MDA-PCa-2b PCa cells connecting metastatic behavior in PCa to observable behaviors in osteoclast activity. Human peripheral blood mononuclear cells were cultured and differentiated over a 14-day period, and co-cultured with PC-3 or MDA-PCa-2b cells for 5 days. Brightfield microscopy imaging and TRAP enzyme activity in cell culture supernatant were used to record the progression of osteoclast differentiation. At the study endpoint, cell morphology and differentiation were confirmed using brightfield imaging, TRAP staining, and immunocytochemistry. qPCR analysis was used to quantify osteoclastic gene expression. We expect PC-3 cells will increase TRAP activity and markers of osteoclasts differentiation compared to MDA-PCa-2b cells in co-culture groups. This study will enhance our understanding of the mechanisms through which PCa destabilize skeletal homeostasis, allowing for better refinement of intervention strategies and treatment plans.