The Mark Foundation for Cancer Research (MFCR) has awarded five new grants in support of an important, emerging approach to cancer therapeutics. The projects are centered around the molecular strategy of induced proximity, which involves controlling the physical distance between proteins to regulate or perturb biological processes in the cancer cell.
One of the biggest challenges in developing new cancer therapies is that many proteins are not tractable to the traditional approach in drug discovery of directly inhibiting the function of a therapeutic target. The induced proximity model aims to overcome this hurdle by altering the target protein's function without requiring that small molecules be direct inhibitors.
Substantial efforts are already under way to design drugs that harness cellular machinery for the degradation of specific targets, a strategy known as targeted protein degradation (TPD). These drugs, which include proteolysis-targeting chimeras (PROTACs) and molecular glue degraders, use bifunctional small molecules to connect target proteins with cellular modifiers that lead to their breakdown within the cell. More recent advances in induced proximity include methods that result in apoptosis, phosphorylation, and epigenetic modulation, all of which are promising avenues for cancer therapy.
In January 2020, MFCR brought together experts in chemical biology, drug discovery, and cancer biology in a workshop to envision new strategies for cancer therapeutics based on induced proximity. The workshop, organized by Daniel Nomura, PhD, from University of California, Berkeley, and Becky Bish, PhD, from MFCR, was attended by scientists from the United States and abroad who brainstormed new and innovative approaches within this therapeutic category. Attendees represented academic institutions as well as biotechnology companies.
Today, MFCR is announcing that it has awarded four grants that arose from the January meeting, as well as one additional grant. All five projects are designed to support high-risk, high-reward research that addresses key feasibility and proof-of-concept questions.
The following ASPIRE awards were selected in a competitive request for proposals that followed the January meeting:
- Amit Choudhary, PhD, and his team from Harvard Medical School are exploring whether small molecules called phosphorylation-inducing chimeric small molecules (PHICS), which bring kinases into close proximity with a target proteins, can enhance phosphorylation in cancer targets. The ultimate goal is to use aberrant phosphorylation to evoke an immune response.
- Arvin Dar, PhD, and his lab at the Icahn School of Medicine at Mount Sinai have developed a compound dubbed "trametiglue," a version of the FDA-approved MEK inhibitor trametinib, that has enhanced interfacial binding properties. These improved properties show promise in overcoming the resistance that's commonly seen with trametinib. Trametiglue and its analogs are being used as research tools and studied as potential leads for new therapeutics.
- H. Courtney Hodges, PhD, of the Baylor College of Medicine, and Nate Hathaway, PhD, of the University of North Carolina, are collaborating to develop bifunctional small molecules that can activate SWI/SNF-dependent transcriptional enhancers. SWI/SNF is an important chromatin remodeling complex that can lead to cancer when inactivated.
- Benjamin Stanton, PhD, of Nationwide Children's Hospital and The Ohio State University College of Medicine, and his collaborator Jun Qi, PhD, of Dana-Farber Cancer Institute, are developing induced proximity-based precision therapeutics for rhabdomyosarcoma that result in the degradation of the drivers of oncogenic transcriptional programs in this rare pediatric solid tumor.
An additional induced proximity project was selected for MFCR's new Drug Discovery Partnership program, which is designed to accelerate the trajectory of promising scientific discoveries towards becoming therapeutics that will benefit cancer patients.
- Craig Crews, PhD, is leading a team at Yale School of Medicine to continue developing a TPD approach for treating chordoma, a rare cancer of the spine and skull base. The foundation for this work in the Crews lab originated in a successfully completed study funded by a Therapeutic Innovation Award jointly granted by MFCR and the Chordoma Foundation in 2018.
At The Mark Foundation, we are always excited to learn how the most innovative thinkers are applying the latest technology advances to tackling challenges in cancer. The recipients of these awards demonstrate the type of out-of-the-box problem solving that we believe will translate to new therapies and tools that can substantially move the field of cancer research forward."
Michele Cleary, PhD, MFCR CEO