Funded in memory of Patty Molloy.
Pancreatic cancer is one of the most lethal cancers and has a five-year survival rate of ~9%. This outcome is largely due to limitations in current diagnostic strategies as well a lack of effective therapies. Thus, there is a dire need to better understand this disease. Recent studies in cancer research have indicated a causal relationship between the capacity of cancer cells to cope with stress and cancer progression and therapy resistance. Pancreatic tumors are driven by a gene called KRAS that is mutated in 95% of all human pancreatic cancers. We have recently found that one critical process driven by mutant KRAS is the formation of stress granules. Stress granules serve as a protective mechanism from chemotherapeutic agents, which kill cancer cells by inducing stress. In this proposal, my laboratory will determine the role of stress granules in the drug resistance of KRAS-driven pancreatic cancer, and develop strategies to block stress granules as a therapeutic tool. This approach has not been explored and could provide impactful insight for the treatment of this disease.
Funded by the Stuart Scott Memorial Cancer Research Fund
Pancreatic ductal adenocarcinoma (PDAC) is a uniformly lethal cancer with a five-year patient survival rate of fewer than eight percent. This dismal statistic is caused in part by the inability to detect PDAC early enough for surgical resection and PDAC tumors do not respond to standard chemotherapies. Ninety-five percent of PDAC tumors have an activating mutation in the gene KRAS. Despite 30 years of research invested in anti-RAS therapies, it is still not possible to directly inhibit RAS clinically. Hence, research has focused on identifying cellular processes that help KRAS mutant cancers grow, survive, and resist treatment with chemotherapies. One cellular process that mutant KRAS turns on in PDAC is autophagy, which is a process of ‘self-eating’ in which cells digest themselves in order to recycle building blocks needed as fuel sources for aggressive growth. Chloroquine, a drug that blocks autophagy, reduces PDAC tumor growth in preclinical models and clinical trials. In addition, the tumor-inhibiting effects of gemcitabine, a frontline chemotherapeutic for advanced PDAC, are enhanced when autophagy is decreased with chloroquine. However, chloroquine blocks autophagy non-selectively, requires high doses, and turns on autophagy when treatment is prolonged. Therefore, alternative autophagy inhibitors are needed. Recent studies in our lab discovered that limiting the availability of the transition metal copper to KRAS mutant cells reduces autophagy and in turn tumorigenic properties. Thus, the proposed studies will address whether copper-reducing drugs used to lower copper levels in humans can be repurposed for the treatment of KRAS mutation-positive PDAC by blocking autophagy.
Cancer is caused by genetic changes (errors), making every cancer unique. Nevertheless, cancers share features that allow them to be grouped into categories or “subtypes.” A tumor’s subtype strongly influences its behavior, including growth rate, likelihood of responding to one therapy versus another, and probability of relapse. Knowing each tumor’s subtype could thus help determine which therapy is best for a give a patient, a concept known as “Precision Medicine.” Currently, subtype can only be determined by in-depth sequencing of tumor tissue, and thus it is not routinely determined in clinical practice.
The goal of this proposal is to develop a rapid, non-invasive, and inexpensive way to determine tumor subtype from a blood test. This is called “liquid biopsy,” and it is playing an increasingly important role in cancer care. Because liquid biopsies are non-invasive (i.e. they do not require surgery or other procedures), samples can be obtained repeatedly over a course of therapy, allowing better clinical decisions to be made.
Colorectal cancer (CRC) is the second-leading cause of cancer death in the United States, where it has a disproportionately lethal effect on African-Americans. Recently, a consensus panel concluded that the disease has four major subtypes based on patterns of gene expression (which genes are “on” or “off” in the tumors). In this proposal, we will use these
definitions to perform subtyping from liquid biopsies. In the future, the approaches we will develop here will be applicable to all cancers, not just those affecting the colon and rectum.
Funded by the Dick Vitale Gala in Memory of John Saunders
Immunotherapy has given hope to many patients with previously incurable cancers. One of the strongest new immunotherapy techniques is CD19-targeted cell therapy. This is a method of engineering T cells from a patient to attack their own cancer. B-ALL, a type of leukemia, is the most common cancer in kids. In B-ALL, CD19-targeted cell therapy has put over 90% of relapsed patients into remission within a month of receiving these engineered T cells. One problem is that some patients’ cancers learn to hide the CD19 target that these engineered T cells see. The lack of the target allows the cancer to hide from the T cells and come back. This can happen in more than 20% of patients. With this grant, we will explore an alternative target called CD22. CD22 is on more than 90% of B-ALL cells. We will use a combination of CD19-targeted T cells and a drug called inotuzumab that attacks CD22 to prevent the cancer cells from coming back, even if they can hide the CD19 target. We will also develop T cells to target CD22. First, we will move forward with a combination approach using the CD19 cells and the CD22 drug in B-ALL patients. Later, we may use T cells against both CD19 and CD22. Currently, bone marrow transplant is the best option for kids with relapsed disease, but this comes with many risks. As we increase the number of patients remaining in long-term remission with these cell therapies, we can see a future where fewer patients need to undergo the risks of bone marrow transplant.
Funded by the Jimmy V Celebrity Golf Classic
In honor of Kathy O’Brien
Funded by Papa John’s International
Funded by UNICO Foundation
In memory of Salvatore Bernardi
Mailing List
