Posted on 10/05/2025 5:24:59 PM PDT by ConservativeMind
Researchers have identified potential new therapeutic strategies for patients with advanced melanoma who no longer respond to immunotherapy—an aim representing one of the most pressing clinical challenges in cancer care today.
The study, led by Mohammed Kashani-Sabet, M.D., builds on years of foundational work to better understand the biological basis of resistance to immune checkpoint blockade (ICB) therapies.
The findings form the basis of a forthcoming investigator-initiated clinical trial.
Using transcriptomic profiling and high-throughput drug screening made possible by the Cancer Avatar Program, Dr. Kashani and team analyzed tumors from 14 patients whose melanoma had progressed after PD-1-based immunotherapy compared with tumors from 15 treatment-naïve patients. They identified several druggable genes and pathways, including those involved in mitogen activated protein kinase (MAPK) signaling, angiogenesis and apoptosis, and tested combinations of U.S. FDA-approved drugs targeting these pathways in patient-derived xenograft (PDX) models.
One combination, cobimetinib + regorafenib (Cobi+Reg), showed synergistic anti-tumor activity across multiple melanoma subtypes, including BRAF-, NRAS- and NF1-mutant tumors. The regimen also reversed key resistance mechanisms, including restoring antigen presentation and increasing infiltration of activated CD8+ T cells.
"Cobi+Reg not only shrank tumors in preclinical models—it reactivated the immune system," says Dr. Kashani-Sabet. "This opens the door to combining targeted therapy with immunotherapy for even greater benefit."
The study was conducted as part of the CPMC Cancer Avatar Program, a precision oncology initiative that uses living tumor models to guide treatment decisions. The project has already led to multiple clinical trials.
A CPMC-led clinical trial testing the promising combinations identified in patients with immunotherapy-resistant melanoma is now in development and is anticipated to begin enrolling patients by late 2025.
(Excerpt) Read more at medicalxpress.com ...
A clinical trial is enrolling patients over the next few months, with more information at the source.
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