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Test to Predict Effectiveness of Docetaxel Treatment for Prostate Cancer (NIH Technology Transfer)


Summary Over the past two years, medical oncologists have added three new therapies to the therapeutic arsenal against Castration-Resistant Prostate Cancer (CRPC): abiraterone, Sipleucel-T, and cabazitaxel. Before approval of these agents, docetaxel was the only life-extending therapeutic option for men with CRPC, and docetaxel remains the standard of care for men who can tolerate chemotherapy. Moreover, there are several promising agents that are likely to be FDA-approved for CRPC in coming years (i.e., MDV-3100, EPI-001, and TOK-001). Therefore, the commercial availability of a method to determine which CRPC patients will have a superior response to docetaxel therapy (and which CRPC patients will not respond), will allow medical oncologists to consider other approved options in certain patients, thereby “personalizing” CRPC therapy. The National Cancer Institute (NCI) has developed a genotype test that can indicate the duration of survival following docetaxel therapy in men with CRPC. The test detects a genetic variant in cytochrome P450 1B1 (CYP1B1*3; 4326C>G) that encodes a leucine-to-valine amino acid substitution, L432V, in the translated protein. This genetic polymorphism causes P450 1B1 *3 to synthesize higher than normal concentrations of a reactive estrogen species (e.g., estradiol-3,4-quinone [E2-3,4Q]) that reduces docetaxel activity via two distinct mechanisms. Firstly, E2-3,4Q binds directly to docetaxel at biological pH, thereby reducing docetaxel potency. Secondly, E2-3,4Q antagonizes the mechanism of action of docetaxel (i.e., microtubule stabilization), by destabilizing the interaction between tubulin thiol groups that are required to form microtubules. Therefore, a simple genotypic test can determine whether or not a patient will respond to docetaxel, or whether treatment with other newly-approved anticancer agents is warranted. The genetic marker CYP1B1*3 could be used as a prognostic tool to predict survival rate and propensity to respond to docetaxel treatment. This invention is the subject of filed patent applications US20100280084A1 and EP1943358, and HHS Reference Number E-307-2005/0. Project Goals The focus of this topic is to advance development of this genetic test which would provide rapid and useful a priori predictions of the clinical outcome of docetaxel patients and guide the therapeutic strategy for each patient. The short-term goals of this project are to: (i) develop a rapid and reproducible assay for the CYP1B1*3 variant; (ii) provide additional preclinical evidence necessary for carrying the CYP1B1*3 genotype test into the clinical setting; and (iii) determine if cabazitaxel activity is related to the CYP1B1*3 allele and reactive estrogen species. The long-term goal of this project is obtain FDA approval for the test, to establish broader utility for the CYP1B1*3 test in treatment of other cancer types, implement the test in conjunction with alternate therapeutics that act via modulation of this estrogen responsive pathway, and to further translate the utility of the genotype test to wider clinical use. This technology, once demonstrated in the field of prostate cancer, could be applied to breast and lung cancer genetic markers that have clinical application in defining the chemotherapeutic treatment schedules for individual patients. Phase I deliverables include technique development, further demonstration of the mechanism of CYP1B1*3 interference, validation that genotype is related to survival using retrospective CRPC patient samples, and identification of the percentage of samples with the variant. A future Phase II SBIR award would include a genotype-directed prospective clinical trial with docetaxel and/or cabazitaxel to demonstrate improved taxane outcomes in genotyped patients. This is an NIH TT (Technology Transfer) contract topic from the NCI. This is a program whereby inventions from the NCI Intramural Research Program (Center for Cancer Research, CCR) are licensed to qualified small businesses with the intent that those businesses develop these inventions into commercial products that benefit the public. The contractor funded under this contract topic shall work closely with the NCI CCR inventor of this technology. The inventor will provide assistance in a collaborative manner with reagents and discussions during the entire award period. Between the time this contract topic is published and the time an offeror submits a contract proposal for this topic, no contact will be allowed between the offeror and the NCI CCR inventor. However, a pre-submission public briefing and/or webinar will be given by NCI staff to explain in greater detail the technical and licensing aspects of this program (for further information, see In addition, a list of relevant technical, invention, and licensing-related questions and answers (including those from the public briefing) will be posted, maintained, and updated online ( during this time period. The awarded contractor will automatically be granted a royalty-free, non-exclusive license to use NIH-owned and patented background inventions only within the scope and term of the award. However, an SBIR offeror or SBIR contractor can apply for an exclusive or non-exclusive commercialization license to make, use, and sell products or services incorporating the NIH background invention. Offerors submitting an SBIR contract proposal in response to this topic are strongly encouraged to submit concurrently an application for a commercialization license to such background inventions. Under the NIH NCI TT program, the SBIR contract award process will be conducted in parallel with, but distinct from, the review of any applications for a commercialization license. To apply for a commercialization license to develop this NIH invention, an SBIR offeror or SBIR contractor must submit a license application to the NIH Licensing and Patenting Manager: Sabarni Chatterjee, Ph.D., or 301-435-5587. A license application and model license agreements are available at and This license application provides NIH with information about the potential licensee, some of the terms desired, and the potential licensee's plans for development and/or commercialization of the invention. License applications will be treated in accordance with Federal patent licensing regulations as provided in 37 CFR Part 404. A further description of the NIH licensing process is available at NIH will notify an SBIR offeror who has submitted an application for an exclusive commercialization license if another application for an exclusive license to the background invention is received at any time before such a license is granted. Any invention developed by the contractor during the course of the NIH TT contract period of performance will be owned by the contractor subject to the terms of Section 8.5. Phase I Activities and Expected Deliverables • Develop a simple array-based genotyping technique for CYP1B1*3 in which a genotype call is conferred to the patient within two days following the receipt of a blood sample • Extend the proof-of-concept that CYP1B1*3 interferes with docetaxel activity via formation of estrogen quinones using cellular assays and/or tumor-bearing mice • Validate that the genotype is related to survival in retrospective samples obtained from patients with CRPC undergoing therapy with docetaxel (The NCI intramural laboratory can aid in getting samples) • Identify the percentage of patient samples with the CYP1B1*3 variant • Determine if cabazitaxel is subject to the same interaction with E2-3,4Q (The NCI intramural laboratory has synthesized frozen E2-3,4Q and can provide some of the quinone estrogen species; it is unlikely that the NCI laboratory could provide any retrospective samples) • Deliver data to the NCI Phase II Activities and Expected Deliverables • Conduct a genotype-directed prospective clinical trial with docetaxel and/or cabazitaxel to demonstrate improved taxane outcomes in genotyped patients (The NCI may provide samples from retrospective studies and assist with getting more samples) • Identify the percentage of patients with the CYP1B1*3 variant • Translate the test to the commercial clinical setting in a manner sufficient to pass CLIA certification • Develop a commercially-viable prototype
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