We officially launched the Foundation in September 2017. In a few short months, and thanks to our partners, sponsors, and donors, we raised $150,000 for prostate cancer research. These funds which will be used to fund three cutting-edge research grants. After a thorough review of submitted research proposals, we awarded three $50,000 grants to research projects at the UAB Comprehensive Cancer Center.
The Mike Slive Foundation is committed to being good stewards of support received from our partners, sponsors, and donors. Only 10% of our expenses go toward overhead, with 90% going toward our mission of “saving lives by funding cutting-edge research and by raising awareness of prostate cancer.” For details, please review our Form 990.
INVESTIGATOR: SUNIL SUDARSHAN, MD, PHD
Dr. Sudarshan is a urologic surgeon-scientist dedicated to the further understanding of the molecular basis on genitourinary malignancies and to translate these findings to the development of novel treatments that will impact the care of affected patients. His particular area of interest is the role the TET enzyme (ten-eleven translocation methylcytosine dioxygenases) to prostate cancer. Dr. Sudarshan believes this grant will validate the finding that the loss of the TET protein promotes the development of aggressive prostate cancer. Dr. Sudarshan will determine how TET is lost, and how it can be turned back on. Identifying the target genes of TET will allow the documentation of the characterization of protein and their effects on prostate cancer progression. This in turn will lead to new and novel therapeutic approaches to the disease.
INVESTIGATORS: WENDY DEMARK-WAHNEFRIED, PHD, RD (PROFESSOR OF NUTRITION SCIENCES), SOROUSH RAIS-BAHRAMI, MD (ASSISTANT PROFESSOR OF UROLOGY AND RADIOLOGY), ROBERT OSTER, PHD (PROFESSOR OF MEDICINE), AND ANDREW FRUGÉ, PHD, RD (AUBURN UNIVERSITY)
Obesity is a clear risk factor for 13 different cancers, but for prostate cancer, this relationship is complex. The most recent data shows that is related to aggressive prostate cancer, prostate cancer progression and prostate cancer death. These data come from many observational studies in humans, as well as experiments in preclinical models. Dr. Demark-Wahnefried and team will be studying randomized controlled trial data on weight loss among obese and overweight prostate cancer patients to determine if slower weight loss/or less intensive physical activity exerts a beneficial impact on tumor biology. In addition, they will to determine if rapid weight loss fuels the aggressiveness of tumor growth in the prostate. The NCI-supported trials (one in breast cancer and one in prostate cancer) of weight loss interventions convened during the presurgical period yielded incredibly interesting results that suggest that a slow, steady weight loss that includes exercise may be the best to reduce prostate cancer cell proliferation. Through additional testing of RNA expression data and some circulating biomarkers, we hope to better understand the mechanisms by which slow weight loss and exercise may help men with prostate cancer and arrive at some idea of the rate of weight loss and the amount and kind of exercise needed.
INVESTIGATOR: KESHAV K. SINGH, PH.D.
The androgen receptor plays a central role in the normal development of the prostate gland, in prostate carcinogenesis, and in the progression of prostate cancer to advanced metastatic disease. Nuclear localization of androgen receptor upon binding to testosterone directs regulation of a host of nuclear genes. Traditional thinking is that nuclear localization of androgen receptor plays a key role in prostate tumorigenesis. Although this is certainly true, we have discovered that additional action(s) of androgen receptor outside the nucleus can contribute to prostate cancer. Surprisingly, we have found that the besides in the nucleus androgen receptor localizes into mitochondria and contains authentic mitochondria localization signal capable transporting other proteins into the mitochondria. Our study suggests that mitochondria-localized androgen receptor is a novel player in promoting prostate tumor growth and metastasis. It is conceivable, that androgen receptor in mitochondria acquires novel mitochondrial function(s) and provides energy needed to fuel prostate cancer aggressiveness, but this remains to be investigated. This grant will seek to 1) determine the novel function(s) of androgen receptor in the mitochondria and evaluate the tumor growth and metastatic potential of mitochondria-localized androgen receptor in mouse xenograft model.
INVESTIGATOR: SAMUEL GALGANO, MD ASSISTANT PROFESSOR, DEPARTMENT OF RADIOLOGY, UAB
Prostate cancer is common and affects about 1 in 10 men. However, there is considerable variation in how prostate cancer progresses. Some prostate cancers are slow-growing and do not pose a threat to life while others are more aggressive and require early treatment to avoid spread of cancer and death. In contrast to localized disease, the 5-year survival for patients with distant metastatic disease is 29%. This is largely because it is difficult to detect disease outside the prostate at the time of diagnosis using conventional imaging. CT and MRI require that lymph nodes become enlarged before they are suspicious for having cancer within them, however normal size lymph nodes can also harbor cancer. If suspicious lymph nodes could be detected at the time of initial diagnosis regardless of their size, additional radiation to these lymph nodes would potentially decrease the rates of cancer recurrence and more effectively treat metastatic cancers. Thus, there is a great need for more accurate staging of extra-prostatic disease at the time of initial diagnosis to guide therapy and thereby reduce the rates of recurrence and death from prostate cancer.
This project proposes to use a novel molecular imaging method that detects Prostate-specific membrane antigen (PMSA-PET), in combination with MRI to identify metastatic prostate cancer at the time of diagnosis. The objective of this study is to (1) demonstrate that PSMA-PET/MRI can detect more lymph node metastases than CT or MRI alone and (2) to evaluate the ability for the radiation oncologist to use the results from this PET/MRI to provide additional radiation to suspicious lymph nodes. After getting the results of the PSMA-PET/MRI, the radiation oncologist will be able to design a unique radiation treatment plan for each patient and evaluate if it is possible to give extra radiation to the suspicious lymph nodes. If the treatment plan is feasible, the radiation oncologist will deliver additional radiation to the suspicious lymph nodes in addition to standard radiation treatments.
INVESTIGATORS: SUZANNE LAPI, PHD PROFESSOR, DEPARTMENT OF RADIOLOGY, UAB JONATHAN MCCONATHY, MD, PHD ASSOCIATE PROFESSOR, DEPARTMENT OF RADIOLOGY, UAB
Obesity is a clear risk factor for 13 different cancers, but for prostate cancer, this relationship is complex. The most recent data shows that is related to aggressive prostate cancer, prostate cancer progression and prostate cancer death. These data come from many observational studies in humans, as well as experiments in preclinical models. Dr. Demark-Wahnefried and team will be studying randomized controlled trial data on weight loss among obese and overweight prostate cancer patients to determine if slower weight loss/or less intensive physical activity exerts a beneficial impact on tumor biology.
The wide spectrum of aggressiveness of prostate cancer presents major clinical challenges, leading to overtreatment of slow-growing prostate cancers and undertreatment of more aggressive prostate cancers. This study proposes the creation of a new targeted treatment that delivers cancer-killing radiation directly to prostate cancer cells. LAT1is a protein that is associated with aggressive, castration-resistant prostate cancers but has low levels in most normal tissues. These properties make LAT1 a very promising target for PET imaging and for targeted therapy. In mouse models of prostate cancer, LAT1 levels were detected and quantitated with high sensitivity and specificity using a LAT1 antibody.
In this proposal, radioactive elements (the lutetium-177 and yttirum-90) will be attached to the LAT1 antibody which will then home to prostate cancer cells and deliver radiation in a very focused manner. For men with cancers that have spread beyond the prostate gland with high levels of LAT1, our approach can be used to selectively deliver lethal radioactivity to metastatic prostate cancer cells. This therapy could be used with established prostate cancer therapies such as androgen deprivation and chemotherapy. A key advantage of this approach is the use of PET imaging to select patients most likely to benefit from the therapy based on the presence of the LAT1 target. Support from the Mike Slive Foundation will be used to create the lutetium-177 and yttirum-90 labeled therapeutic agents and to perform therapy studies in mouse models to determine if they can be used to treat prostate cancer. Our long term goal is to translate the most promising agents into first-in-human studies in an effort to better target effective treatments for patients with high levels of LAT1.
INVESTIGATOR: SELVARANGAN PONNAZHAGAN, PHD PROFESSOR, DEPARTMENT OF PATHOLOGY, UAB
The androgen receptor (AR) protein promotes aggressive growth and metastasis of prostate cancer (PCa). New drugs are designed to target AR to inactivate its function, but unfortunately spontaneous mutations and reactivation of other receptor proteins in AR family enable progression and patients die from metastatic disease. Further, when PCa develops resistance to androgen deprivation therapy, it promotes oxidative stress causing cells to become much more aggressive than the slow-growing primary tumor. Hence, development of novel therapies should focus on identifying, and using inhibitors that can overcome these limitations without provoking resistance.
In a preclinical mouse model of PCa, this proposal will test a unique approach using a biologically produced molecule called endostatin. So far, endostatin is known to arrest the growth of blood vessels that supply oxygen and nutrients to the growing tumor. However, recently we made a striking discovery that endostatin efficiently internalizes into PCa cells and binds to AR, causing a significant decrease in AR levels and its tumor-promoting functions. We also found that endostatin could bind to an alternate receptor (GR) that is activated in resistant PCa cells. Indeed, endostatin significantly reverses oxidative stress mechanisms within PCa cells by arresting GR functions. Thus, we strongly believe that endostatin can be effectively used in combination with existing therapies (e.g. enzalutamide and docetaxel) to increase patient survival. Combination therapy with endostatin is expected to reduce the growth of resistant tumors not only by arresting AR and alternate receptor functions, but also by blocking the growth of tumor blood vessels. Hence, this combination therapy will act as a double-edged sword against the growth of tumors that are resistant to current therapies.
INVESTIGATOR: LIZHONG WANG, MD, PHD ASSOCIATE PROFESSOR, DEPARTMENT OF GENETICS, UAB
In the United States, prostate cancer is the second-leading cause of cancer-related death of men. Lethal prostate cancers can be defined as tumors that spread to other organs, such as the bones, lungs, and liver. Several studies have reported mutations in two genes, MYC and PTEN, that accelerate the aggressive metastasis of prostate cancer to such organs. In our preliminary studies, we developed a metastatic prostate cancer mouse model that contains mutations similar to those found in lethal prostate cancer in humans. Analysis of the cancers from this model suggested a synergy between the two altered genes and the first evidence that this synergy occurs through the increased expression of specialized, secreted proteins called CXCL3/7 that help the tumor escape the body’s anti-tumor immune responses and facilitate the spread of cancer to distant organs. Therefore, our central hypothesis is that the dysfunction of MYC and PTEN promote escape and spreading of prostate cancer cells through increases in the secreted CXCL3/7 proteins. Our overall goal is to define the molecular mechanism underlying the synergy between these genes that cause the tumors to spread. We are also focused on improving existing therapeutic strategies for patients who are suffering from lethal prostate cancer. In this proposed work, we will use animal models to determine the role and mechanism of two altered genes that underlie the regulation of CXCL3/7 proteins that promote the spreading of prostate cancer. We will validate the abnormalities detected in the lethal, spreading prostate cancers, and our results will help to guide therapy for men who suffer from cancers of this type. If our hypothesis is validated, our discoveries will immediately help doctors develop more effective treatment options for patients with lethal prostate cancer.