The Epidermal Growth Factor Receptor (EGFR) gene mutations can be detected in about 15% of patients with lung cancers. In female lung cancer patients who have never smoked cigarettes, as many as 50% of patients have this EGFR mutation. These mutations in the EGFR gene can be different from patient to patient, but all lead to the generation of an active protein that drives cells to survive, proliferate, and become cancerous. Currently, we have efficacious drugs for some of the EGFR mutations, but many other mutations do not have an approved drug. To address this unmet need, I am leading a clinical and translational research program including multiple clinical trials aiming to bring new approvals to treat those atypical EGFR mutations lung cancers. We will collect clinical information and bio-samples (both blood and tissue) to understand why some tumors respond to a certain drug, whereas other tumors not, to characterize the landscape of resistance mechanisms for each group of EGFR mutations. We will test a number of novel drug-drug combinations to overcome resistance and provide more potential options for EGFR mutation lung cancer patients. In this program, we will take a team approach to engage investigators with different expertise, use leading-edge technologies, including computational biochemical approaches and single-cell transcriptomics analysis, and ultimately nominate future therapeutic options for patients.
The study will detect cancer of the prostate in African-American men. African American men develop prostate cancer at a young age. The cancer spreads rapidly making it difficult to treat. Our method will detect substances produced by prostate cancer. The test will examine blood collected from men who have concerns with their prostate. The study will develop the test and make it available in the clinic. The test will help African American men in the community who do not have access to medical care. Early finding of prostate cancer will provide enough time for cure and will help reduce cancer related suffering and death.
Renal medullary carcinoma (RMC) is a rare but deadly kidney cancer that mainly occurs in young individuals of African descent that carry a blood disorder called sickle cell trait. Most people carrying the sickle cell trait never develop any symptoms. Many do not even know that they have it. Approximately 1 in 14 African Americans have the sickle cell trait and are at risk for developing RMC at an average age of 28 years old. RMC is also an under-recognized global health challenge because the sickle cell trait is found in ~300 million individuals around the world, mainly in Africa. Almost every patient with RMC is diagnosed late, when the cancer has already spread to other organs. Less than 5% of these patients survive beyond 3 years. Furthermore, many patients with RMC are initially misdiagnosed and lose precious time while being treated with the wrong therapies. The chances of a cure considerably increase when RMC is diagnosed and treated early. With the help of our patient advocates, we have established the largest collection of blood and tissue samples from patients with RMC worldwide. Using these samples, we have found evidence that patients with RMC have antibodies against unique proteins found only in cancer. We have developed a novel technology that allows the detection of more than 400,000 of these antibodies using only a drop of blood, quickly (within 3 days) and affordably. Our proposal aims to investigate and develop this new approach for the early diagnosis of RMC.
Funded by the Dick Vitale Pediatric Cancer Research Fund in memory of Colby Young
Children with changes in a pair of related genes (named DROSHA and DICER1) can get cancer in their lungs, muscles, kidneys, brains, and other organs. This is because DICER1 and DROSHA normally turn off pro-growth signals. When these pro-growth signals cannot be turned off, cancer can arise. We do not know which pro-growth signals are most important. Our lab found that one of these pro-growth signals, named Igf2, may be one of the most important. We came across this idea through studying mice that develop brain cancer due to Drosha changes. This project will study how important Igf2 is. It will also examine exactly how Igf2 gets turned on. Lastly, it will test whether a drug that targets Igf2 will be effective in these cancers.
Lung cancer is a deadly disease. One common cancer treatment called immunotherapy boosts the body’s natural defenses to fight the tumor. However, while some lung cancer patients respond well to immunotherapy treatments, other patients do not respond to the therapy. This suggests that we need to find new ways to improve these treatments. Our research supported by the V Foundation aims to improve the body’s ability to fight lung cancer. We will study mechanisms to boost the effects of immunotherapy and we will test these new approaches using cancer models. This work has the potential to improve immunotherapy and expand the use of these treatments for larger numbers of lung cancer patients.
Breast cancer is the most common type of cancer in women, causing many deaths each year. When the cancer has spread in the person’s body, the available treatments have many side effects and often cannot cure the disease. Research has shown promising results using immunotherapies, which make the patient’s own immune system attack the cancer. T cells are important cells of the immune system and can be very effective at attacking and killing cancer cells. Some breast cancers have a protein called HER2 that can be used as a target for T cells to attach. We plan to take the patient’s own T-cells and train them in the laboratory to attack breast cancer cells that have HER2. This treatment has proven safe in other cancer types and should have minimal side effects. However, breast cancer tumors are made up of different kinds of cells, not just cancer cells. Thus, we also plan to arm the T-cells with extra measures to get rid of the other bad cells in the tumor, making it easier for the T cells to eliminate all of the cancer. Based on previous research, we know that when successful, results using this kind of T cell-based therapy are long lasting for patients and can even cure their disease. With the recent FDA approval of T-cell therapies for several cancers, we are confident that the proposed project has the potential to improve the lives of patients with breast cancer.
Funded by the KAAB Memorial Foundation and the Stuart Scott Memorial Cancer Research Fund
Cancer kills millions of people every year. The deadliest cancers are those that have high rates of metastasis.Metastasis is the movement of cancer cells from one organ site to another. Many of the current therapies aredesigned to kill cancer cells from the original tumor but not the secondary tumors that follow. We find genes responsible for normal embryonic development are improperly present in tumors but not in normal adulttissue. Many of these abnormally expressed genes control activities required for successful invasion andmigration to distant organ sites. The purpose of the proposed research project is to comprehend how tumorsuse these embryonic genes to become metastatic and resistant to chemotherapy. This research will ultimatelyenable researchers to better target these aggressive gene programs, leading to increased patient survival andhopefully eradication of the metastases. My training as a cancer and developmental biologist puts me in aunique position to tackle these difficult questions. The medical community has finally realized that there willnot be one treatment for cancer and each tumor is as unique as the individual is. Therefore, we must thinkoutside the box to design therapies that target genes that responsible for growth, resistance to chemotherapyand metastasis. This current project seeks to understand why developmental pathways are re-expressed as wellfind ways to specifically target these pathways to inhibit metastasis.
Funded by the Constellation Gold Network Distributors
Cancer cells divide rapidly. To be able to do this, cancer cells often rewire their metabolism to produce more building blocks of life- proteins, nucleotides, and lipids. Our lab studies a molecule known as NADPH, which is necessary for the production of these building blocks. We recently discovered that NADPH produced in the mitochondria is essential for the synthesis of an amino acid called proline. Cancer cells that are deficient in an enzyme called NADK2, which maintains mitochondrial NADPH levels, cannot synthesize proline and fail to grow under low proline conditions.
Our analysis of proline production in mice showed that the pancreas makes the most proline. We propose that pancreatic tumors strongly depend on proline and that blocking proline uptake and production should kill pancreatic cancer cells. In the proposed work, we will test whether inhibiting proline production through targeting NADK2 together with the removal of proline from the diet is an effective strategy in reducing pancreatic tumor growth. To test this, we will use a mouse model that mirrors pancreatic cancer. This research will pave the way for new ways to treat patients that have pancreatic cancer and this treatment strategy has the potential to be applied for other cancer types that rely on proline for growth.
The term DNA damage response (DDR) inhibitors is used in cancer treatment to refer to a group of drugs, which block important processes that cancers rely on to repair their DNA. While PARP inhibitors (a type of DDR inhibitor) are approved, they do not benefit all patients, and their effects are not long-lasting. Combining PARP (or other DDR inhibitors) with drugs that may boost their effects is a promising approach, which has been shown in laboratory studies (cancer cells or animal testing) to be more effective than each drug given alone. My program of DDR inhibitor combination trials aims to benefit patients with cancers with defects in DDR and other important processes by matching them with suitable DDR inhibitors in combination with carefully selected drugs, therefore personalizing cancer treatment for each patient. Multiple new and promising DDR inhibitor combinations will be tested. Trials not well-tolerated or effective will be stopped early, while trials with promising combinations will be increased in size. We will personalize these treatments for each patient by studying their cancer/blood samples to ensure that the genetic defects of the tumor match the combination treatment, so as to increase the chance of success. If patients stop responding to treatment, they will be allowed to switch to a different DDR inhibitor combination guided by fresh analyses of new cancer/blood samples. This program of trials aims to advance our DDR scientific knowledge, improve outcomes for each patient and guide future trials in order to get better treatments approved.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Fund
Scientists have given immune cells a detector forB-cell acute lymphoblastic leukemia (ALL).Theycalled these cells CAR T cells. In some patients, these CAR T cells disappear before they can clear the tumor. In others, these cells become too exhausted to work. We have recently identified the molecular code that prevents T cells from dying off or becoming exhausted. With the funding support, we will use this molecular code to make CAR T cells stay in cancer patients longer and clear B-cell ALL more effectively.We hope to use this strategyto cure a much larger population of pediatric cancer patients with B-cell ALL.
