DEPARTMENT OF UROLOGY

Research Faculty Bio

  • kumar photoA. Pratap Kumar, Ph.D.

    Professor

    Email: kumara3@uthscsa.edu
    Phone: (210) 567-5647
    Fax: (210) 567-6868
    Specializing in Translational Science
    Faculty Profile

    Research Goals of the laboratory:

    While cancer deaths have dropped in the US, the human and financial cost of treatment has skyrocketed during this period. Therefore the old adage, ‘prevention is better than cure’ is the motto of our laboratory. We develop primary, secondary and tertiary chemoprevention approaches against cancer. To achieve this goal, we use a two-pronged approach- firstly we identify deregulated molecular mechanisms involved in development, progression and dissemination of cancer and secondly we develop chemoprevention/intervention strategies to target the identified mechanisms for clinical translation.

    Project 1: High-grade prostate intraepithelial neoplastic lesions (HGPIN) are precursor lesions of prostate cancer. Since these lesions take decades to progress to clinical cancer, our efforts are focused on strategies to prevent the progression of HGPIN lesions. Anecdotal and epidemiological observations provide compelling evidence for beneficial effects of the calorie restriction mimetic resveratrol (RES) in preventing cardiovascular diseases and cancer. Our recently published work shows that RES intervention reduces the number of HGPIN lesions. A project to develop RES to prevent clinical prostate cancer by targeting HGPIN lesions via SIRT1-mediated autophagy is currently under investigation.

    Project 2: Androgen-independent prostate cancer is the most aggressive and less understood form of prostate cancer. There is a great need to find strategies to prevent progression to hormone-independent state. Ongoing efforts in our lab have led to the identification of a transcriptional network in androgen-independent prostate cancer as well as compounds that can be used as tools to target players involved in the network and prevent the development of this fatal form of prostate cancer.

    Project 3: Radiation therapy is an important modality to treat early, localized prostate cancer. Many side effects such as radiation proctitis, rectal toxicity, impotence, gastro-intestinal bleeding and urinary dysfunction affect the quality of life of patients. Further development of resistance to radiotherapy is an additional obstacle in this treatment modality. A seminal discovery from our laboratory regarding the utility of Nexrutine® (a naturally occurring bark extract from Phellodendron amurense) as a possible radio-sensitizer led to a clinically relevant translation project to test the safety of Nexrutine® in prostate cancer patients undergoing radiation therapy. This collaborative project between UTHSCSA/CTRC investigators showed Nexrutine® is well tolerated with no grade 3 toxicity. About 81% of patients showed reduction in PSA during the neo-adjuvant portion of the trial. Current work is focused on identifying the molecular mechanism through which Nexrutine® radiosensitizes resistant prostate cancer cells.

    Project 4: We are also developing biomarkers to distinguish indolent vs. aggressive prostate cancer. Identification of a panel of markers that can accurately predict aggressive disease will allow patient stratification and save men with sluggish disease the financial cost and mental agony of cancer diagnosis. Discoveries from our laboratory in collaboration with UTHSCSA/CTRC investigators identified a combination of markers (patent pending) is an excellent predictor of biochemical recurrence. Ongoing studies are examining whether this biomarker signature can predict risk of aggressive disease in ethnic groups at high risk for prostate cancer.

    Project 5: Pancreatic cancer is a disease of near equal mortality. Current literature suggests that fibrosis may be an impediment for clinical management of pancreatic cancer patients. Our group has identified a potential role for GLI transcription factors in mediating the interaction between pancreatic stellate cells (stroma) and pancreatic cancer cells in fibrosis development. On the translational side we are screening natural compounds that inhibit markers of fibrosis in vitro and a preclinical animal model of pancreatic cancer. Collaborative efforts with transplant surgeons at UTHSCSA/CTRC are focused on developing lead compounds in conjunction with conventional therapy for effective management of pancreatic cancer.

    Education outreach: An important goal of the Kumar laboratory is to ensure that we produce the best next generation of cancer prevention scientists. Students who have graduated from my laboratory are receiving additional postdoctoral training at prestigious institutions in the country including Yale University and MD Anderson Cancer Center.

    Selected publications:

    1. Hambright HG, Meng, P, Kumar AP and Ghosh R (2015) Inhibition of PI3K/AKT/mTOR axis disrupts oxidative stress-mediated survival of melanoma cells. Oncotarget, 6(9): 7195-208. PMCID: PMC 25749517.
    2. Yun H, Xie J, Olumi AF, Ghosh R and Kumar AP. (2015). Activation of AKR1C1/ERβ induces apoptosis by downregulation of c-FLIP in prostate cancer cells: A prospective therapeutic opportunity. Oncotarget (in press). PMID: 25816367
    3. Swanson, GP, Jones WE., Ha, CS., Jenkins, CA., Kumar, AP and Basler, J. (2014). Tolerance of Phellodendron amurense barks extract (Nexrutine®) in human prostate cancer patients. Phytotherapy Research doi: 10.1002/ptr.5221. [Epub ahead of print]PMID: 25205619.
    4. Gong, JJ., Xie, J., Bedolla, R., Rivas, P., Chakravarthy, D., Freeman, JW., Reddick, R., Kopetz, S., Peterson, A., Wang, H., Fischer, SM. and Kumar, AP. 2014. Combined targeting of Stat3/NFkB/Cox-2/EP4 for effective management of pancreatic cancer. Clinical Cancer Research. 20: 1259. This article was selected as highlights of the issue.
    5. Gong, JJ., Munoz, AR., Chan, D., Ghosh, R and Kumar, AP. 2014. STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth. Oncotarget. 5: 2529.
    6. Thapa, D., Meng, P., Bedolla, R., Reddick, RL., Kumar, AP and Ghosh, R. (2014). NQO1 Suppresses NF-kB–p300 Interaction to Regulate Inflammatory Mediators Associated with Prostate Tumorigenesis. Cancer Research, doi: 10.1158/0008-5472.CAN-14-0562. PMC4184940
    7. Li, G., Rivas, P., Bedolla, R., Thapa, D., Reddick, RL., Ghosh,R and Kumar, AP. 2013. Dietary resveratrol prevents development of high-grade prostatic intraepithelial neoplastic lesions: involvement of SIRT1/S6K axis. Cancer Prevention Research (Phila). Jan;6(1): 27-39. PMID: 23248098.

    Primary, secondary and tertiary prevention are three terms that map out the range of interventions available to health experts
    Prevention includes a wide range of activities — known as “interventions” — aimed at reducing risks or threats to health. You may have heard researchers and health experts talk about three categories of prevention: primary, secondary and tertiary. What do they mean by these terms?

    Primary prevention aims to prevent disease or injury before it ever occurs. This is done by preventing exposures to hazards that cause disease or injury, altering unhealthy or unsafe behaviours that can lead to disease or injury, and increasing resistance to disease or injury should exposure occur. Examples include:

    1. legislation and enforcement to ban or control the use of hazardous products (e.g. asbestos) or to mandate safe and healthy practices (e.g. use of seatbelts and bike helmets)
    2. education about healthy and safe habits (e.g. eating well, exercising regularly, not smoking)
    3. immunization against infectious diseases.

    Secondary prevention aims to reduce the impact of a disease or injury that has already occurred. This is done by detecting and treating disease or injury as soon as possible to halt or slow its progress, encouraging personal strategies to prevent reinjury or recurrence, and implementing programs to return people to their original health and function to prevent long-term problems. Examples include:

    • regular exams and screening tests to detect disease in its earliest stages (e.g. mammograms to detect breast cancer)
    • daily, low-dose aspirins and/or diet and exercise programs to prevent further heart attacks or strokes
    • suitably modified work so injured or ill workers can return safely to their jobs.

    Tertiary prevention aims to soften the impact of an ongoing illness or injury that has lasting effects. This is done by helping people manage long-term, often-complex health problems and injuries (e.g. chronic diseases, permanent impairments) in order to improve as much as possible their ability to function, their quality of life and their life expectancy. Examples include:

    • cardiac or stroke rehabilitation programs, chronic disease management programs (e.g. for diabetes, arthritis, depression, etc.)
    • support groups that allow members to share strategies for living well vocational rehabilitation programs to retrain workers for new jobs when they have recovered as much as possible.

    Current projects:

    Transcriptional regulation of FLIP during prostate carcinogenesis:

    Studies from our laboratory identified a non-toxic estrogen metabolite namely 2-methoxyestradiol as an inhibitor of prostate tumor development in pre-clinical animal model that is associated with down regulation of FLIP. Studies also identified a critical role for transcription factor Sp1/Sp3 in the regulation of FLIP during prostate carcinogenesis (Clinical Cancer Research 2006 and 2009). Studies are in progress to investigate precise mechanism of FLIP de-regulation during development of hormone-refractory prostate cancer including the role of transcription factors and their interactions and microRNA’s.

    Development of natural products for cancer management:

    Studies from our laboratory identified Nexrutine®, a bark extract from cork-tree (Phellodendron amurense) that inhibits prostate tumor development in a pre-clinical animal model. These studies further identified inhibition of transcriptional activation of Cox-2 through Akt mediated activation of CREB as a potential mechanism for the observed biological activities (Neoplasia, 2006 and 2007; Clinical Cancer Research 2007; The Prostate 2009; Anticancer Research 2010). Currently studies are in progress to develop Nexrutine® as an agent for prostate cancer management either by itself or in combination with existing standard of care due to its ability to target Akt/mTOR signaling axis.

    Studies are also in progress to develop Nexrutine® for pancreatic cancer management specifically targeting EP receptor signaling.

    Development of combinatorial approaches:

    Studies are ongoing to understand the molecular events associated with development of metastatic prostate cancer to develop as targets for prostate cancer management using combination of agents.

    For post-doctoral or research assistant positions, please contact kumara3@uthscsa.edu

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