Although childhood cancer survival rates have improved over the past 40 years, pediatric acute myeloid leukemia (AML) is still very difficult to treat successfully. This is partially because the immune system has a hard time recognizing and killing AML cells. Though white blood cells usually fight infections or cancer, certain types of “tumor-permissive” white blood cells (APCs) make it easier for cancer to escape being recognized by the immune system. These tumor-permissive APCs send out signals to other immune cells telling them to relax and not kill leukemia cells. Our research goal is to find ways to make these APCs stop sending tumor-permissive signals, so that the immune system can recognize AML cells better and get rid of the leukemia. Specifically, we found that APCs use a protein called MerTK to send tumor-permissive signals to other immune cells. When we block MerTK using a new orally-active drug, APCs stop sending tumor-permissive signals and instead, start sending new signals that tell other immune cells to fight leukemia. MerTK drugs are headed to clinical trials for their anti-cancer effects; our research demonstrates that these drugs could also be used to boost the immune system against cancer. With this grant, we will investigate the cellular steps involved in blocking MerTK, so that we can determine how to use MerTK inhibitors most effectively to treat pediatric patients with AML. We hope to show that this novel therapy will help improve pediatric AML survival rates and patient’s quality of life.
Lung cancer is the leading cause of cancer death in the US and worldwide with 15-18% cure rate. Thus, prevention is a critical strategy to decrease lung cancer deaths. Tobacco smoking causes the large majority of lung cancer and smoking cessation is the best intervention in smokers; however, the risk of lung cancer in former smokers remains high. The administration of drugs or natural products to prevent cancer is called chemoprevention. Unfortunately, currently, no drug, natural product or vitamin has been shown to decrease lung cancer incidence in humans.
The prostacyclin analog, iloprost, prevents lung cancer in mice exposed to tobacco smoke, as well as other chemicals. Therefore, we performed an early phase clinical trial of iloprost in humans. Iloprost improved airway changes that lead to lung cancer in humans, but only in former, not current, smokers. 59% of former smokers given iloprost improved airway dysplasia compared to 29% given placebo. Our goal is to be able to identify those former smokers who will benefit from iloprost so as to treat the right patients with the right drug. We have developed a patient-derived epithelial progenitor cell culture that can lead to such a test, as it recapitulates the morphologic improvement in dysplasia. Preliminary data suggest that gene expression differs between iloprost responders and non-responders at baseline. If we can develop a biomarker to discriminate responders from non-responders, future clinical trials can be accelerated and if positive, iloprost chemoprevention can be targeted to the correct subset of former smokers.
Recipient of the V Scholar PLUS Award, a third year of grant support for V Scholars who have made exceptional progress in year 1 and 2 of their original grant
The precision oncology approach to the treatment of cancer bases treatment decisions on the biology of an individual’s cancer, most often using genetic alterations or mutations to inform therapy. This approach has been successful in a few cancer types, including lung cancer, melanoma, and chronic myelogenous leukemia where oral targeted therapies have led to both improved patient outcomes and fewer side effects compared to standard chemotherapy. However, this approach has not yet realized its full potential in these or other cancer types. In this proposal we plan to study new cancer-causing gene mutations involving the NTRK1, NTRK2 and NTRK3 genes, which are found in numerous types of cancer. We have already demonstrated that tumor cells treated with targeted therapies against this gene family can kill cancer cells in the laboratory. We have also observed early and dramatic tumor shrinkage in patients with different tumor types that share mutations in these NTRK genes. This proposal will focus on determining additional mutations of NTRK genes that may respond to therapy. The proposal will also study how cancer cells become resistant to targeted therapies and develop new laboratory models of NTRK+ cancer to develop new therapies for these cancers.
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