Chemokine-based Approaches to Treat Immunologically "Cold Tumors”

Wednesday, April 5, 2023

4:00 PM-5:30 PM

BIOMED Seminar

Title:
Chemokine-based Approaches to Treat Immunologically "Cold Tumors”

Speaker:
Gabriele Romano, PhD
Assistant Professor
Department of Pharmacology and Physiology
Drexel University
College of Medicine

Details:
Patients with BRAF-mutant melanoma show significant responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment.

Computational analysis identified candidate T-cell recruiting chemokines that may be central players in the process, being strongly upregulated initially and steeply decreasing as the immune response faded. Therefore, we hypothesized that sustaining the chemokine signaling could impair MRD maintenance through increased recruitment of effector T-cells.

We show that intratumoral administration of recombinant Cxcl9, either naked or loaded in microparticles, significantly impaired MRD relapse in BRAF-inhibited tumors, including several complete responses after microparticle-delivered rCxcl9 combined with BRAF and MEK-inhibition. Our experiments constitute a proof of concept that chemokine-based microparticle delivery systems are a potential strategy to forestall tumor relapse and thus improve the clinical success of frontline treatment methods.

Biosketch:
Gabriele Romano, PhD, is currently an Assistant Professor in the Department of Pharmacology and Physiology at the Drexel University College of Medicine (Philadelphia, PA). The primary focus of the lab is to detail the molecular mechanisms involved in cancer drug resistance and the identification of effective counter-therapies. A major clinical issue in cancer treatment is the occurrence of intrinsic or acquired drug resistance. Genetic or epigenetic alterations and microenvironment stimuli can modify the signaling wiring of cancer cells and can either cause upfront resistance to therapy or be the leading force driving tumor cell evolution towards a resistant phenotype.

Dr. Romano's lab research framework is at the crossroads of Cancer Modeling and Experimental Therapeutics, aiming to create a bench-to-bedside platform to counteract cancer drug resistance. This approach uses a unique synergy of immunocompetent mouse models, bioinformatics, and functional genomics, to uncover mechanisms "missed" by standard-of-care treatments and propose rational-based synergistic strategies.

Dr. Romano's approach is intrinsically multi-disciplinary and non-compartmentalized, as his career goal is to tackle long-standing clinical issues with complex models representing the real nature of the problem. To achieve the goals, he is supported by an incredibly talented and diverse team of graduate and undergraduate students. His lab prides itself on advancing biomedical science while fostering the growth of the scientists of tomorrow and promoting an equitable research environment.

Contact Information

Lisa Williams
ltw22@drexel.edu