Game-Changing Collaboration Will Accelerate Cancer Vaccines
Read moreState: Texas
Thomas Westbrook, Ph.D.
Sendurai Mani, Ph.D.
Ju-Seog Lee, Ph.D.
Funded by The V Foundation Wine Celebration Vintner Grant
In honor of Robin Lail
James Brugarolas, M.D., Ph.D.
Funded by the Jimmy V Celebrity Golf Classic Volunteer Grant
In honor of Dave and Wanda Farley
Benjamin Deneen, Ph.D.
Kenneth D. Westover, M.D., Ph.D.
Funded by The Michael and Carole Marks Family
Multiple lines of evidence suggest that if achievable, inhibiting K-Ras signaling may have therapeutic advantages in cancer. Approximately 30% of all human cancers contain activating Ras mutations making them one of the most common identifiable molecular cancer drivers. Despite almost 30 years of effort, direct inhibitors of Ras family members have failed to achieve success in the clinical setting. Our immediate aim is to develop and evaluate GTP-competitive inhibitors of K-Ras. Our long term goal is to apply this concept to other cancer-related small GTPases and test it as a new therapeutic strategy.
Targeting the GTP binding site of Ras is difficult because it binds to GTP and GDP with high affinity and the intracellular concentrations of GTP and GDP are also high. We recently reported a concept to overcome these obstacles that involves using compounds that form a covalent bond with K-Ras after they enter the GTP binding site. This concept was motivated both by clinically important, time-tested covalent inhibitors like aspirin and penicillin and by recently developed, rationally designed covalent kinase inhibitors such as Ibrutinib and Afatinib which are now FDA approved. Our prototype compound, SML-8-73-1 (SML), is a GDP analogue containing a reactive warhead extending from the beta-phosphate which adds irreversibly to Cysteine 12, a cysteine found in the active site of an oncogenic mutant form of K-Ras that is common in people exposed to cigarette smoke, K-Ras G12C. We have shown that even in the presence of large excesses of GDP and GTP, quantitative complete irreversible binding of SML is observed.
We hypothesize that for non-G12C K-Ras mutants and other cancer-related GTPases the covalent strategy may be applied by targeting a conserved active site lysine. We already know that targeting this lysine with covalent chemistry is possible but we don’t know if this strategy can be adapted to make inhibitors that are selective for particular GTPases and what the impact of these compounds will be on GTPase-mediated signaling. The goal of our work supported by the V Foundation will be to explore this concept by generating and testing new compounds which target the conserved active site lysine.
Keith Syson Chan, Ph.D.
Funded by the Jimmy V Celebrity Golf Classic
Volunteer Award In honor of
Dave Gibson and Felicia Davis
Kenneth Westover, M.D., Ph.D.
V Scholar Plus Award- extended funding for exceptional V Scholars
Cancer is an abnormal state wherein cells become uncontrolled in their ability to divide, grow and cross tissue borders. These cellular processes are governed by an array of signaling proteins including KRAS. Mutations in the KRAS protein result in uncontrolled signaling leading to cancer. KRAS mutations are some of the most common causes of many types of cancer. However, researchers have struggled to discover ways of treating tumors driven by mutant KRAS. The goal of this project is to develop new drugs that directly target mutant KRAS proteins. We will focus on two mutations. One is common in lung cancer, KRAS G12C. The other is common in gastrointestinal cancers, KRAS G13D.
Leonid Metelitsa, M.D., Ph.D.
Funded by the Buster and Kristen Posey Fund
with Recognition to Dick Vitale
In this project, we aim to develop a safe and effective treatment for a childhood cancer called neuroblastoma. Recently, there has been some success harnessing the human immune system to fight cancer. We have developed an immune-based strategy to target one specific cancer-promoting gene that is known to cause an aggressive form of neuroblastoma. This gene is present in about half of all cases with poor disease outcomes in our patient population. We developed a new cancer vaccine for this gene that causes immune cells in the body to fight cancer cells directly. A mouse version of this vaccine proved safe and potent in mice, so we think we can use the same strategy to create a clinical-grade vaccine that will be safe and effective in humans, too. In this study, we first will test each part of this vaccine separately and then will re-assemble them in a very clean laboratory room. Indeed, this vaccine will be produced under such strict conditions that it will be ready for clinical testing in children with neuroblastoma after this grant is completed. Because we are targeting a gene that is expressed on cancer cells but not on cells of healthy tissues, our vaccine is unlikely to be as toxic as others treatments that are available now in the clinic. This vaccine is easy to deliver, as it can be swallowed and so does not involve a shot, making it easier for pediatric patients.
