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Principal Investigator: GREGORY A CLINES
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
Prostate cancer is the most common deadly cancer of men. Bone metastasis is a painful complication of
advanced prostate cancer associated with significant morbidity. Endothelin-1 (ET-1) is a prostate cancer-
secreted factor that activates the osteoblast endothelin A receptor (ETAR) causing osteoblast proliferation and
pathologic new bone formation. In turn, osteoblasts send chemotactic and growth cues back to the prostate
cancer cells. Preliminary data have unexpectedly demonstrated that ablation of both ET-1 and androgen action
in osteoblasts is necessary to reduce bone lesion growth in castrate-resistant prostate cancer (CRPC).
Furthermore, osteoblast generation of active androgens from adrenal dehydroepiandrosterone (DHEA) further
fuels osteoblast-directed prostate cancer progression in bone.
The goals of this proposal are to investigate the actions of ET-1 and androgen on tumor burden in an
animal model prostate cancer bone metastasis in three specific aims. Aim 1 will examine the effects of
castration and DHEA replacement combined with ETAR blockade in a “humanized” animal model of prostate
cancer bone metastasis. Scid mice will undergo castration or sham surgery, and treatment with the ETAR
antagonist zibotentan or a vehicle control. The effects of sustained-release DHEA to negate the effects of
combined zibotentan and castration on the development of prostate cancer skeletal lesions will be tested. It is
expected that DHEA treatment, in castrated mice treated with ETAR blockade, will increase the development
and/or size of prostate cancer lesions in bone compared to control mice not receiving DHEA. Aim 2 will
examine the effects of Hsd3b7 knockout on the progression of prostate cancer bone lesions in DHEA-treated
mice. It is hypothesized that the protein encoded by Hsd3b7 is responsible for osteoblast conversion of DHEA
to androstenedione, and androstenediol to testosterone. It is expected that knockout of Hsd3b7 will negate the
effects of DHEA on the development of prostate cancer lesions in castrated mice treated with ETAR blockade.
Aim 3 will determine if combined ETAR blockade and androgen depletion prevents the initiation of skeletal
lesions, the progression of established lesions, or both. The combination of castration and ETAR
pharmacologic blockade reduced the number of skeletal lesions in a mouse model of bone metastasis
compared to either alone. The timing of androgen depletion and ETAR blockade required to reduce skeletal
tumor burden is unknown. Male scid mice will undergo castration or sham surgery before inoculation of tumor
cells or at the point when skeletal lesions have been established. It is expected that the combination of
androgen depletion and ETAR blockade will prevent both the initiation and the progression of established
lesions.
ADT is the standard treatment in men with metastatic prostate cancer, but disease progression to CRPC
and bone metastases in most men mark the fatal form of the disease. The clinical implication of this research is
that ETAR blockade may be effective only with maximal androgen blockade. These findings generated by this
proposal will be a catalyst for clinical trials to reduce the morbidity and mortality of CRPC in veterans.
Terms: <2,4,D/2,4,5,T><4-Androstene-3,17-dione><5 alpha-Dihydrotestosterone><5-alpha-DHT><Ablation><Acetates><Adrenal Glands><Adrenals><African American group><African American individual><African American people><African American population><African Americans><Androgenic Agents><Androgenic Compounds><Androgens><Androst-4-ene-3,17-dione><Androstanolone><Androstenediols><Androstenedione><Androstenolone><Animal Model><Animal Models and Related Studies><Back><Bone Cancer><Bone Development><Bone Formation><Bone Formation Stimulation><Bone Metastasis><Bone cancer metastatic><Bony metastasis><Cancers><Castration><Cell Communication and Signaling><Cell Signaling><Cessation of life><Clinical><Clinical Trials><Complication><Compressive Myelopathy><Cues><DHEA><Data><Death><Dehydrogenases><Dehydroisoandrosterone><Delta 5-Androstenediol><Development><Diagnosis><Dihydrotestosterone><Disease><Disease Progression><Disorder><Dorsum><Drug Targeting><EDN1><ET-1><Endothelin A Receptor><Endothelin Type 1><Endothelin-1><Endothelin-1 Receptor><Enzyme Gene><Enzymes><Fracture><General Population><General Public><Generalized Growth><Generations><Goals><Growth><Hermaphrodiol><Human><Hydroxysteroid Dehydrogenases><Intracellular Communication and Signaling><Isoenzymes><Isoforms><Isozymes><Knock-out><Knockout><Laboratories><Lesion><Malignant Bone Neoplasm><Malignant Neoplasms><Malignant Osseous Neoplasm><Malignant Osseous Tumor><Malignant Tumor><Malignant Tumor of the Bone><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Metastasis><Metastasis to bone><Metastasize><Metastatic Cancer to the Bone><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Bone><Metastatic Prostate Cancer><Metastatic Tumor><Metastatic Tumor to the Bone><Metastatic malignant neoplasm to bone><Mice><Mice Mammals><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><Neoplasm Metastasis><Operative Procedures><Operative Surgical Procedures><Osseous Cancer><Osseous metastasis><Osteoblasts><Osteogenesis><Osteosclerotic Lesion><Oxidoreductase><Oxidoreductase Gene><Pain><Painful><Pathologic><Prasterone><Prostate CA><Prostate Cancer><Prostate Carcinoma Metastatic><Prostate malignancy><Prostatic Cancer><Protein Isoforms><Proteins><Radiation therapy><Radiotherapeutics><Radiotherapy><Reductases><Reporting><Research><Residual><Residual state><Role><SCID Mice><Secondary Neoplasm><Secondary Tumor><Secondary cancer of bone><Secondary malignancy of bone><Secondary malignant neoplasm of bone><Severe Combined Immunodeficient Mice><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skeletal metastasis><Skeleton><Stanolone><Steroid Compound><Steroids><Surgical><Surgical Castration><Surgical Interventions><Surgical Procedure><Testing><Testosterone><Therapeutic Androgen><Therapeutic Androstanolone><Therapeutic Androstenedione><Therapeutic Dehydroepiandrosterone><Therapeutic Testosterone><Tissue Growth><Trans-Testosterone><Tumor Burden><Tumor Cell><Tumor Load><Veterans><Viet Nam><Vietnam><Xtandi><abiraterone><advanced prostate cancer><agent orange><androgen ablation therapy><androgen blockade therapy><androgen deprivation therapy><androgen deprivation treatment><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><antagonism><antagonist><biological signal transduction><bone><bone fracture><bone neoplasm secondary><bone tissue formation><cancer diagnosis><cancer metastasis><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><catalyst><compare to control><comparison control><dehydroepiandrosterone><delta-4-Androstenedione><developmental><enzalutamide><hormone refractory prostate cancer><humanized mice><humanized mouse><improved><intratumoral androgen><male><malignancy><men><military veteran><model of animal><mortality><mouse model><murine model><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><osteoblast proliferation><pain reduction><pharmacologic><prevent><preventing><prostate cancer cell><prostate cancer metastasis><prostate cancer model><prostate cancer progression><prostate cancer resistant to androgen><prostate cancer risk><prostate tumor cell><prostate tumor model><radiation treatment><reduce pain><resistance mechanism><resistant mechanism><sham surgery><skeletal><skeletons><social role><spinal cord compression><standard care><standard treatment><suprarenal gland><surgery><treatment with radiation><tumor cell metastasis><veteran population>