The saying goes that a society grows great when people plants trees that they will never sit under. The Wisconsin Breast Cancer Showhouse (WBCS) leads in this investment in the future with their seed funding to promising researchers. Seed money helps a researcher to bridge an idea into a hypothesis and then into experiments that become the building blocks of greater research. Many times, the projects seem small but their ramifications on future health outcomes can be sizable.
Carmen Bergom, MD, PhD is a cancer researcher who has benefited from a WBCS investment. The overarching goal of Dr. Bergom’s lab is to identify novel molecular targets to improve and personalize breast cancer care. Previous research on treatment personalization in the breast cancer has led to breakthroughs in the systemic treatment of breast cancer, such as anti-estrogen and Her2-targeted therapies. However, no similar tumor information has been utilized to better direct the use of radiation therapy. Radiation therapy can improve overall survival in both early stage cancers and more advanced breast cancers, and more than 50% of the 230,000 breast cancer patients diagnosed annually will receive radiation. Dr. Bergom received a grant from WBCS that aimed to identify changes in breast tumors that led to improvement in radiation responses.
This work by Dr. Bergom’s lab has identified changes in the blood vessels of tumors that can improve the responses to radiation therapy in pre-clinical models of breast cancer. They have also found that these blood vessel changes can be enhanced with therapeutic interventions. The pathways identified as important in the tumor vasculature are currently being validated to determine whether they are therapeutic targets to enhance the radiation response in breast cancer in patients. The laboratory has since expanded these studies using similar models to identify how some of these changes also affect the radiation responses of normal tissues that can receive incidental radiation exposure as part of breast cancer therapy, most notably the heart.
The research that the initial seed money funded will now be expanded via a $1.2 million 5-year award from the National Institutes of Health to study ‘Genetic Modifiers of Radiation Therapy-induced Cardiotoxicity’. Dr. Bergom’s translational research program has the long-term goal of using innovative genetic tools to study the key pathways in the tumor microenvironment and breast tumor cells that are used to evade therapy, and to identify pathways that are important for radiation toxicity to organs such as the heart and lungs. The overall goal is to improve the efficacy of radiation therapy in breast cancer, while minimizing the side effects from the radiation therapy. The development of predictive tools for the radiosensitivity of tumors could better guide the doses of radiation administered or lead to the use of treatments in conjunction with radiation for tumors that are more resistant to radiation thereby furthering better care for future patients.e.
2019 WBCS Research Awardees
Marja Nevalainen, MD, PhD, Professor, Pathology and Pharmacology & Toxicology
Research Title: "Stat5 and Anti-Androgen-Induced Metastatic Phenotype of Prostate Cancer"
Treatment options for metastatic prostate cancer (MPC) are limited to androgen-deprivation therapy. The new-generation anti-androgen, Enzalutamide dominates the clinical space and is FDA approved in pre- and post-chemotherapy settings. Resistance to Enzalutamide arises within 3-6 months, with patients developing terminal castrate-resistant (CR)-MPC. There are no effective therapies for CR-MPC. Our data support a novel concept that Stat5 promotes development of Enzalutamide-resistant prostate cancer (ERPC). We previously showed that Stat5 induces metastatic behavior of PC cells. Also, Enzalutamide has been shown to induce metastatic phenotype of PC. Our new data show that Enzalutamide induces Jak2-Stat5 activation in PC. This proposal will test whether Enzalutamide induction of Jak2-Stat5 signaling in PC mediates Enzalutamide promotion of CR-MPC and may result in a new therapeutic strategy for ERPC by exploiting Jak2-Stat5 pathway inhibitors that are in clinical development for leukemias. Our goal is that this project results in development of a new therapy for ERPC.
Marcelo Bonini, PhD, Associate Professor, Medicine-Endocrinology
Research Title: “Metabolic regulation of immunity in the tumor microenvironment”
Tumors grow because their environment shields them from destruction by the immune system. To create an immunosuppressive environment, tumors recruit macrophages. Macrophages are immune cells that are capable of both activating immunity to eliminate tumors or creating an immunosuppressive barrier. Somehow, macrophages that become associated with tumors lose their capacity to activate and rather suppress the immune response. The mechanisms used by tumors to make macrophages act this way are unknown. Our novel hypothesis is that cancer cells release lactate, a metabolite produced by them in large amounts, to force macrophages to become immunosuppressive. Our preliminary data indicate that macrophages immersed in lactate lose their capacity for immune activation while assuming an immunosuppressive phenotype. Hence, this application aims at furthering the idea that lactate secretion by tumors serves the purpose of immunomodulation to co-opt tumor associated macrophages to protect rather than attack cancer.
Amit Joshi, PhD, Associate Professor, Department of Biomedical Engineering
Research Title: ““Personalized Nanomedicine Interventions Targeted to Germline Driven Tumor Vascular Heterogeneity”
Breast cancer affects 1 in 10 US women in their lifetime. Current treatment for breast cancer involves surgery, chemotherapy and radiation treatment. These treatments not only cause undesirable side effects, but there is also a high level of inconsistency in how patients respond to treatment even in similar disease types. We suggest that part of this variation in treatment response might be due to inherited genes controlling the blood vessel development in tumors. Patients with favorable inherited blood vessel behavior in tumors have higher drug delivery to tumors, and favorable treatment response, while in others, genetically inherited factors predispose them to more aggressive and therapy resistant tumors. In this proposal, we will address both the low efficacy and side effects of current breast cancer treatments by personalizing treatment through a novel nanoparticle based imaging/therapy approach. We will target inherited blood vessel development controlling genes, to avoid therapy resistance and aggressive behavior in patients with unfavorable inherited genes.
In October 2017, WBCS committed to fund a $1 million prostate cancer research professorship in support of MCW's advancement of a Prostate Cancer Center of Excellence. The recruitment of Hallgeir Rui, MD, PhD, in 2014 as the WBCS Breast Cancer Research Professor has had a transformational influence on breast cancer research at MCW. That success was a critical component in the decision to fund a prostate cancer research professorship. The decision to fund a second professorship places WBCS in the unique position of sponsoring two professorships at MCW. Both are unique in another way. Our all-volunteer, grassroots organization has both generous corporate and foundation donors and support by individuals from every walk of life. The funds we raise represent a community of supporters who are transforming treatment and advancing research in ways that would otherwise not be possible.