Immune-based medicines are effective in treating and curing subsets of patients across multiple cancers. However, approximately 80% of patients across all cancers fail to respond to immune-based medicines. This lack of clinical benefit is particularly prevalent in aggressive forms of metastatic prostate cancer (MPC) that are resistant to hormonal therapies, where few objective responses to immune-based medicines have been observed.
The immune system is comprised of cells that can both promote and suppress the growth of the cancer. Our research has revealed that the microenvironment within MPC exhibits scarcity of immune cells. Furthermore, the sparse immune cells that reside within the microenvironment of MPC promote tumor growth and progression. Therefore, there is an urgent need to develop medicines that reprogram the tumor-promoting “bad” immune cells to create a more favorable environment, so the “good” immune cells can enter the tumor and kill cancer cells. The goal of our research is to identify and develop new medicines that can achieve this “switch” in the immune system, to enhance recognition and elimination of the most aggressive forms of prostate cancer. We will test these potential medicines in both mouse models of PC in the laboratory, and in patients with the most aggressive forms of MPC enrolled in clinical trials. Collectively, the findings stemming from this proposal will lead to a deeper understanding of the immune escape mechanisms that allow MPC to spread, and advance the clinical development of novel medicines to reinvigorate the body’s immune system to eradicate MPC.
Funded in partnership with the Cancer Research Institute through the V Foundation’s Virginia Vine event and Wine Celebration Fund-A-Need
Diffuse large B cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma in the U.S., is often curable with initial treatment. However, outcomes of the ~40% of patients who experience disease recurrence are dismal. Although stem cell transplantation and CAR T cell therapy salvage a subset of patients, most are not candidates for these aggressive treatments or will relapse after receiving them. Thus, relapsed DLBCL remains a critical area of unmet need. Recently, an immunotherapy that stimulates cancer cell engulfment by macrophages through blocking a “don’t eat me” protein called CD47 has shown promising activity in relapsed DLBCL patients when administered with the anti-CD20 antibody, rituximab. However, only 30-40% of patients achieve lymphoma regression after receiving this treatment. My laboratory has devised innovative approaches to enhance CD47 blockade therapy efficacy in relapsed DLBCL. First, by inhibiting a key signaling pathway in macrophages, we can enhance their “appetite” for DLBCL cells in the context of CD47 blockade in vitro. Second, we have developed tools necessary to execute an unbiased genetic screen to identify new and targetable “don’t eat me” proteins on DLBCL cells that enable their escape from macrophage phagocytosis. The major goals of this application are to: 1) enhance the in vivo efficacy of CD47 blockade therapy in DLBCL by disrupting a key macrophage signaling pathway, and 2) identify new “don’t eat me” proteins on lymphoma cells that can be targeted alone and in combination with CD47 blockade therapy. While DLBCL is our focus, many cancers employ mechanisms to evade engulfment. Thus, our results are expected to have broad cancer relevance.
EMPOWERED U is a community research program to better understand and address the gaps in cancer research in our diverse communities. Black or African American (AA) patients have lower rates of joining cancer prevention or treatment clinical trials. For many cancers, Black or AA patients are still diagnosed later or may not live as long as white patients. Many factors such as insurance, poverty, age, other diseases, racism and bias in treatment, and trust of medical research due to prior racism may cause these differences. As science for cancer treatment advances, the gap will increase if not everyone has equal access to new technology. Patients may miss the chance to join new trials and researchers may miss the chance to better understand disease and treatments in diverse groups.
This program partners directly with community members to study opinions from patients, caregivers, local community leaders, and medical providers to better understand barriers, myths, fears as well as factors that can improve trials participation and the patient experience.
The patient and community voice will be captured in focus groups and interviews. The community research team will use this important input to design a Community Clinical Trials Toolkit (booklets, print cards and videos) to better answer questions and worries and support patients to learn about clinical trials. Importantly, we will also create community led education for providers and clinical research teams about community and patient perspectives and best practices to support patients.
FUNDED BY THE STUART SCOTT MEMORIAL CANCER RESEARCH FUND
Tobacco use, specifically cigarette smoking, is a primary reason that adults develop and die from lungcancer. Adults with low income smoke cigarettes at higher rates than the general population, but they areless likely to go to the doctor and receive help with quitting. It is important to design programs that reachthis population outside of a hospital or clinic setting.
Community health workers (CHWs) are frontline public health workers who work with these communitiesto help improve their health and connect them to medical services. CHWs are often the first, andsometimes the only, healthcare provider for these adults. Training CHWs on conducting briefinterventions for tobacco cessation, or quitting smoking, is important. However, current trainings fortobacco cessation are not always accessible to CHWs because of cost and time-constraints, andbecause the trainings are not relevant to CHWs’ patients’ experiences. This study will address theseissues by adapting a tobacco cessation training specifically for CHWs. We will use information thatCHWs have provided about their practices caring for their patients to make the training relevant to theirpatients’ experiences. We will then give the training to CHWs and test whether the training increasedCHWs’ knowledge about tobacco cessation, and whether the training is appropriate for CHWs and theirpatients. Having more CHWs trained in tobacco cessation will increase the number of adults who receivehelp to quit smoking, which will help to reduce tobacco use and, ultimately cancer, among adults with lowincome.
Funded by the Constellation Gold Network Distributors
Cancer is a disease of uncontrolled cell growth. As the disease advances, the cancer can leave the original site and spread to other parts of the body. The ability to grow and invade is energetically costly though. Thus, cancer cells will modify their metabolism to meet these high energy requirements. This includes aggressively using nutrients to produce more energy (ATP), making building blocks for growth (protein, plasma membranes, DNA) and finding ways to overcome metabolic stress (e.g., reactive oxygen species). In other words, if we can identify metabolic changes that occur only in cancer, then impacting the altered metabolic pathways could enable us to selectively kill cancer cells and not impact normal cells.
We are interested in the metabolism of the sugar molecules fructose and mannose. Cells generate mannose-related metabolites from fructose. We discovered that the balance between fructose and mannose is important when lung cancer becomes aggressive. Only these aggressive lung cancer cells were killed when the conversion of fructose to mannose was disrupted. This project will examine how fructose-mannose metabolism is changed when lung cancer becomes aggressive. We will also determine why this metabolic pathway is critical to keep these cancer cells alive. To accomplish the task, we will remove a critical enzyme in fructose -mannose metabolism, and then utilize a series of experiments to characterize the metabolism of these cancer cells. If successful, this study will provide clues as to why drinking soda (fructose) can increase cancer risk while consuming mannose slows tumor growth. Ultimately, we want to answer whether targeting this sugar pathway can help treat patients.
Funded by the Constellation Gold Network Distributors
Diffuse large B cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, can often be cured with chemotherapy. However, DLBCL will relapse in ~40% of patients. When this happens, currently available treatments are usually not effective. Treatments for relapsed DLBCL also cause many side effects that affect quality of life. Programmed death-1 (PD-1) blockade immunotherapy has been very effective in treating a number of human cancers, and is generally well-tolerated by patients. Unfortunately, PD-1 blockade therapy has not been very effective for patients with relapsed DLBCL. Therefore, we need to define biological markers that identify DLBCL patients who are likely to benefit from this type of treatment. In search of such a marker, we found that DLBCLs with an increased number of genes for the partner of PD-1, known as programmed death-ligand 1, were associated with strong evidence that an immune response had been generated against them. We will now test whether lymphomas with PD-L1 gene duplications will be more likely to shrink after treatment with PD-1 blockade therapy, and we will also attempt to determine what other features of these lymphomas are important in determining whether the immune system can recognize them. We expect that the knowledge gained from our studies will improve outcomes for patients who have DLBCL that has relapsed.
Funded by UNDEFEATED in honor of Chicago Blackhawks and Darlene Shaw
The experimental therapeutic PAC-1, when combined with FDA-approved drugs for metastatic breast cancer, has been found to give a highly synergistic effect on the killing of the breast cancer cells. Given that PAC-1 is already being evaluated in a Phase 1 trial in cancer patients (NCT02355535), these results suggest future combination trials for the treatment of metastatic breast cancer patients.
In recent years, doctors and scientists have recognized that a person’s genetic make-up helps determine their risk for developing particular bone marrow derived cancers. The bone marrow produces all of our blood cells, and the white blood cells that fight infection can be broken down roughly into two classes, myeloid cells and lymphoid cells. Between these two main groups, the DNA changes that confer risk for developing cancers are best defined for myeloid blood cancers, whereas DNA changes associated with lymphoid blood cancers largely remain to be discovered. Drs. Godley, Leavitt, and Wiemels have formed an interdisciplinary team to fill this void. Drs. Godley and Leavitt are hematologists who work directly with patients and families with clustering of lymphoid cancers, and Dr. Wiemels is an epidemiologist who works with large population-based data sets and blood samples to understand factors that put groups of people at risk for disease. Collectively, their work has shown that Hispanic patients are particularly susceptible to developing lymphoid cancers and are more likely to suffer poor outcomes. Drs. Godley and Leavitt have already identified variants in several genes that appear to confer particular risk for developing lymphoid cancers, and these provide a starting point for the proposed studies. The team will be focused in Chicago and California, areas with large Hispanic populations, with the ultimate goal of using genetic risk factors to optimize therapy for patients and to develop preventive strategies to avoid cancer development in high-risk individuals.
