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Inhibitor of Adrenal Steroid Synthesis for Cancer Treatment

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
95920
Program Year/Program:
2010 / SBIR
Agency Tracking Number:
CA150540
Solicitation Year:
N/A
Solicitation Topic Code:
NCI
Solicitation Number:
N/A
Small Business Information
ORPHAGEN PHARMACEUTICALS
11494 Sorrento Valley Road SAN DIEGO, CA 92121-
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2010
Title: Inhibitor of Adrenal Steroid Synthesis for Cancer Treatment
Agency: HHS
Contract: 1R43CA150540-01
Award Amount: $520,358.00
 

Abstract:

DESCRIPTION (provided by applicant): Orphagen has identified antagonists to an orphan receptor that regulates the major biosynthetic steps of steroid hormone synthesis in the adrenal cortex and gonads. Safe and effective inhibition of adrenal steroid syn thesis has a number of potential applications in oncology, including treatment of two rare and very poorly managed conditions. One is life-threatening, uncontrolled glucocorticoid and/or mineralocorticoid release from metastatic adrenocortical carcinoma (A CC). The other is Cushing's syndrome resulting from unresectable ACTH-secreting tumors that stimulate adrenal steroid synthesis without normal hypothalamic feedback. In addition, these novel orphan receptor antagonists are potentially of significant value in the treatment of hormone-dependent prostate cancer as chemical castration does not block release of the adrenal androgens, DHEA and DHEA-S, which contribute significantly to the total androgen load in prostate. The novel approach of specifically antagon izing this critical orphan receptor has the potential to be both safer and more effective than mitotane, ketoconazole and aminoglutethimide, broad spectrum P450 inhibitors currently used for this purpose. We propose in Aim 1 to characterize inhibition of s teroidogenesis by receptor antagonists in cultured adrenal carcinoma cell lines and in primary adrenal cultures, confirming that the antagonists suppress steroidogenesis in cancerous and normal adrenal cells. In Aim 2, we plan to synthesize a metabolically stable tool compound for animal studies by modification of current antagonists, and in Aim 3 we propose to characterize the action of these on adrenal steroidogenesis in mouse. Proof-of-principle studies demonstrating overall efficacy of the novel antagon ists for suppression of adrenal steroidogenesis will provide the framework for further preclinical development as well as the investigation of preclinical models, such as steroid secretion by adrenocortical cancer cell lines, adrenal activation by ACTH-sec reting tumors, and regulation of adrenal androgen production in a non-rodent species. PUBLIC HEALTH RELEVANCE: Abnormal and excessive adrenal steroid production, producing severe abnormalities of metabolism or hypertension, threatens the lives of s everal thousand cancer patients/year. Steroids derived from the adrenal gland also contribute to the spread of prostate cancer, which causes more than 30,000 deaths per year in the U.S. Available therapies are not adequately effective. We have identified s mall molecule antagonists to a novel receptor that exerts broad control over adrenal steroid synthesis. Successful clinical development of these antagonists could markedly improve clinical prognosis for these indications.

Principal Investigator:

Scott M. Thacher
8584816191
SMT@ORPHAGEN.COM

Business Contact:

Scott Thacher
smt@orphagen.com
Small Business Information at Submission:

ORPHAGEN PHARMACEUTICALS
ORPHAGEN PHARMACEUTICALS 11494 Sorrento Valley Road SAN DIEGO, CA -

EIN/Tax ID: 133094369
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No