PREVENTION OF PTEN DELETION DRIVEN PROSTATE CANCER BY SELENIUM
Lu Junxuan
University Of Minnesota Twin Citiescity: Minneapolis country: United States (us)
Grant 5R21CA155522-02 from National Cancer Institute
Keywords: Adenocarcinoma; Age; Aging; AKT Signaling Pathway; American; Animal Model; Atypical hyperplasia; Automobile Driving; Biochemical; Cancer Burden; cancer diagnosis; Cancer Etiology; cancer initiation; Cancer Model; Cancer Patient; cancer prevention; cancer therapy; Cancerous; carcinogenesis; Cell Culture Techniques; Cell Death; Cell Proliferation; Cessation of life; Chemicals; Chemoprevention; Chromosomes, Human, Pair 10; Clinical; clinically relevant; clinically significant; cohort; cost effective; Data; Development; diabetes risk; Dietary Supplements; Disease Progression; dosage; Dose; DU145; Epithelial; Etiology; Failure (biologic function); Future; Generations; Growth; Health Benefit; Histopathology; Human; human data; human disease; Immunohistochemistry; in vivo; indexing; Kinetics; Lesion; male; Malignant neoplasm of prostate; Malignant Neoplasms; Measures; Mediating; men; Metabolic; methylselenic acid; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; National Cancer Institute; Nature; Neoplasm Metastasis; Neurosecretory Systems; Nude Mice; Oral; Oral Administration; Pathway interactions; Perception; Phosphorylation; Physiological; Plant Roots; pre-clinical; Pre-Clinical Model; Premalignant; prevent; Prevention; Preventive; Prostate; Prostate Adenocarcinoma; prostate cancer prevention; prostate carcinogenesis; Prostatic Intraepithelial Neoplasias; Proto-Oncogene Proteins c-akt; PTEN gene; public health relevance; Research; research study; response; Rodent Model; Schedule; Scientist; Selenium; Selenium and Vitamin E Efficacy Trial; Selenium Compounds; Selenomethionine; selenomethylselenocysteine; Signal Pathway; Solid; Staging; Supplementation; Surveys; Techniques; Testing; Tissue Sample; Tissues; Transgenic Organisms; translational study; tumor progression; Validation; Weight; Western Blotting; Work; Xenograft Model; Xenograft procedure
Relevance: The ill-reputed selenomethionine in the Selenium and vitamin E Cancer prevention Trial (SELECT) study has brought a lot of negative publicities on the whole research field of selenium-cancer prevention and treatment. Rigorous studies as proposed here that use a clinically relevant pre-clinical model and a judicious choice of selenium agents with compelling mechanistic rationale and support (unlike the case with SeMet for SELECT) are essential and necessary to produce relevant data to support continued work to realize the full health benefits of the second-generation selenium and change perceptions and understanding of scientists and the public alike on selenium´s merits
Project start date: 2010-12-15
Project end date: 2012-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R21CA155522-02 (2012): $149260
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Lu Junxuan
METHYL-SELENIUM FOR PROSTATE CANCER CHEMOPREVENTION
Lu Junxuan, Professor And Chair
Texas Tech University Health Scis Centercity: Lubbock country: United States (us)
Grant 7R01CA126880-05 from National Cancer Institute
Abstract: The ongoing Selenium-vitamin E Cancer Trial (SELECT) is testing the efficacy of selenium (Se) in the form of selenomethionine (SeMet) alone or in combination with vitamin E to prevent prostate cancer (PCa) in a cohort of some 32,400 North American men. The results are expected in a decade. If a positive preventive efficacy is confirmed, the public health impact of using this form of Se is self-evident, and this will provide an outstanding impetus for further clinical trials to identify more efficacious Se agents to realize even greater preventive benefits. If negative, the quest for effective Se agents takes on significant urgency. Cell culture studies by us and others suggest that methylselenol and its immediate precursors such as methylseleninic acid (MSeA, we refer them collectively as methyl-Se) are much more efficacious than SeMet with respect to a number of anti-PCa processes such as inhibiting angiogenic switch mechanisms, inducing G1 cell cycle arrest, decreasing AKT activation and inducing caspase-mediated apoptosis. We and others have recently shown that methyl-Se inhibits androgen receptor (AR) expression and signaling, which are crucial for PCa development. Furthermore, we have now in pilot studies found that MSeA and methylselenocysteine (MSeC) given by daily oral dosing exerted dose-dependent inhibition of DU145 human PCa xenograft growth in athymic nude mice and SeMet at the same dosage did not. We hypothesize that methyl-Se prevents PCa in vivo by its broad-spectra anti-cancer actions through inhibiting tumor angiogenesis, cell cycle arrest and/or an induction of caspase-mediated apoptosis as well as by the prostate organ-specific inhibition of AR expression and signaling. To test this hypothesis, we propose 3 specific aims in both androgen-dependent (AD) and androgen-independent (AI) PCa xenograft models and the TRAMP (TRansgenic Adenocarcinoma Mouse Prostate) primary prostate carcinogenesis model. We will establish the in vivo chemopreventive efficacy of MSeA and MSeC vs. SeMet and characterize and validate key mechanistic biomarkers such as VEGF suppression for anti-angiogenesis and AR and PSA suppression for inhibition of androgen signaling. We expect to provide valuable efficacy and biomarker data to guide the design of future clinical translational studies with methyl-Se with greater prostate specific targeting actions. They will also be insightful for predicting and interpreting the outcomes of the SELECT study. Narrative The results from these studies will provide valuable in vivo efficacy and biomarker data to guide the design of future human clinical trials for methyl selenium for prostate cancer chemoprevention. They will also be instructive for predicting and interpreting the outcomes of the ongoing selenium cancer prevention trials
Keywords: Acute; Address; Adenocarcinoma; American; Androgen Antagonists; androgen independent prostate cancer; Androgen Receptor; Androgens; Angiogenic Switch; antiangiogenesis therapy; Apoptosis; bevacizumab; biomarker; cancer cell; cancer chemoprevention; Cancer Prevention Trial; cancer risk; caspase; caspase-3; Cell Culture Techniques; Cell Cycle Arrest; Cell physiology; Chemoprevention; Chemopreventive Agent; Clark 1; Clinical; Clinical Trials; cohort; Colon; Data; density; design; Development; dosage; Dose; DU145; efficacy testing; Event; Future; Growth; hormone refractory prostate cancer; Human; improved; In Situ Nick-End Labeling; in vivo; indexing; LNCaP; Lung; Malignant neoplasm of prostate; Malignant Neoplasms; Mediating; men; methylselenic acid; Modeling; Mus; mutant; Nude Mice; Oral; Organ; Outcome; Phosphotransferases; Pilot Projects; prevent; Preventive; Process; Prostate; prostate carcinogenesis; Proto-Oncogene Proteins c-akt; prototype; public health medicine (field); receptor expression; Receptor Signaling; Regimen; research study; Risk Reduction; Role; Secondary Prevention; Selenium; Selenomethionine; selenomethylselenocysteine; Serum; Signal Transduction; Site; Testing; Time; Tissue Sample; Transgenic Organisms; translational study; tumor; Tumor Angiogenesis; Vascular Endothelial Growth Factors; Vitamin E; War; Xenograft Model; Xenograft procedure; Yeasts
Project start date: 2007-09-21
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
7R01CA126880-05 (2011): $273686
AN ORIENTAL HERBAL CAM MODALITY FOR PROSTATE CANCER CHEMOPREVENTION
Lu Junxuan, Professor And Chair
Texas Tech University Health Scis Centercity: Lubbock country: United States (us)
Grant 7R21AT005383-02 from National Center For Complementary & Alternative Medicine
Abstract: Our long term goal is to develop an orally effective, non-toxic alternative and complimentary medicine (CAM) modality from Oriental herbs for prostate cancer (PCa) chemoprevention. We have found that the ethanol extract of Ka-mi-kae-kyuk-tang (KMKKT) consisting of 10 herbs (i) has strong anti-angiogenesis activity; (ii) inhibits the in vivo growth of human PC-3 androgen-independent PCa xenografts in nude mice; (iii) inhibits the in vivo growth of mouse Lewis lung carcinoma allograft; and (iv) inhibits colon cancer-liver metastasis in the mice. And importantly, the above effects of KMKKT were observed without adverse effects on body weight at the doses tested, supporting its excellent safety for long-term use. Given that carcinogenesis is a multi-stage process requiring many genetic and epigenetic alterations, effective preventive measures must selectively target multiple molecular targets and cellular processes important for cancer initiation, promotion, progression and metastasis. We hypothesize that (a) KMKKT will be a safe and effective CAM chemopreventive modality against primary prostate carcinogenesis through anti- angiogenic, cell cycle arrest and pro-apoptotic and anti-metastasis actions; and (b) the herb(s) responsible for the anti-angiogenesis and anti-metastasis activity can be identified to recapitulate this formula with a minimal number of herbs. Our specific aim 1 is to evaluate the chemopreventive efficacy of orally-administered KMKKT against the transgenic adenocarcinoma mouse prostate (TRAMP) model of primary prostate carcinogenesis and metastasis (Lu lab). We will compare the effect of orally-administered KMKKT vs. i.p. injection of KMKKT on genito-urinary (GU) tract weight, dorsolateral prostate (DLP) weight, ventral prostate (VP) and lesion progression in these respective lobes (Year 1) and then we will establish the impact of orally- administered KMKKT given at different stages of prostate lesion development on the long term survival of the TRAMP mice (Year 1-2). Aim 2 is to determine the PCa-relevant anti-angiogenesis and anti-metastasis activities of orally-administered KMKKT and identify active herbs for each activity through a single-herb deletion approached combined with individual herbal evaluation (Kim Lab). Positive chemopreventive efficacy without toxicity with the orally-administered KMKKT cocktail in Aim 1 will be a great impetus for its continued preclinical development to pave the way for planning human translational studies. Successful accomplishment of Aim 2 will enable us to determine, in the future, whether the chemopreventive action of the full formula can be recapitulated by a minimal number of herbs. The identified herbs will be excellent starting points to identify active chemicals for better QC/QA of the herbal CAM products as well as for further pharmacological R&D. Prostate cancer (PCa) is the No. 2 cause of cancer death of men in the US. In spite of the advances in early detection and treatments, there is no cure for the late stage and metastatic disease. Chemoprevention has become recognized as a plausible and cost-effective alternative approach to reduce the morbidity and mortality of PCa. However, due to the complex nature of carcinogenesis, main stream single agent/target-based research has not led to the development of any effective chemopreventive modality for PCa so far. This R21 application specifically focuses on testing an Oriental herbal formula with demonstrable multiple targeting anti- cancer activities to support a paradigm shift to achieve that goal
Keywords: Adenocarcinoma; Adverse effects; Allografting; androgen independent prostate cancer; angiogenesis; Animals; antiangiogenesis therapy; Apoptosis; Apoptotic; Asians; attenuation; base; Biological Assay; Body Weight; cancer chemoprevention; cancer diagnosis; Cancer Etiology; cancer initiation; carcinogenesis; caspase; Cell Culture Techniques; Cell Cycle Arrest; Cell physiology; Cessation of life; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical; Collaborations; college; Colon Carcinoma; Complementary and alternative medicine; Complex; cost effective; cost effectiveness; density; Development; Dietary Supplements; Disease; Dose; Early Diagnosis; Early treatment; Epigenetic Process; Ethanol; Evaluation; Future; Genetic; Goals; Growth; Herb; Herbal Medicine; Human; in vitro activity; in vivo; in vivo Model; Individual; Injection of therapeutic agent; International; Korea; Lesion; Lewis Lung Carcinoma; Lobe; Malignant neoplasm of prostate; Malignant Neoplasms; Measures; Mediating; Medicine; men; Metastatic Neoplasm to the Liver; Modality; Modeling; Molecular Target; Morbidity - disease rate; Mortality Vital Statistics; Mus; Nature; Neoplasm Metastasis; novel; Nude Mice; Oriental Medicine; Pathway interactions; Pharmaceutical Preparations; pre-clinical; Preventive; Probability; Process; product development; professor; Prostate; prostate carcinogenesis; public health relevance; Quality Control; Research; Safety; Screening procedure; Staging; Stream; Targeted Research; Testing; Toxic effect; Transgenic Organisms; translational study; tumor; Universities; Urinary tract; Weight; Xenograft procedure
Relevance: Prostate cancer (PCa) is the No. 2 cause of cancer death of men in the US. In spite of the advances in early detection and treatments, there is no cure for the late stage and metastatic disease. Chemoprevention has become recognized as a plausible and cost-effective alternative approach to reduce the morbidity and mortality of PCa. However, due to the complex nature of carcinogenesis, main stream single agent/target-based research has not led to the development of any effective chemopreventive modality for PCa so far. This R21 proposal specifically focuses on testing an Oriental herbal formula with demonstrable multiple targeting anti- cancer activities to support a paradigm shift to achieve that goal
Project start date: 2010-06-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-08-185
7R21AT005383-02 (2011): $155194