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Targeting Neuroendocrine Prostate Cancer Using Multi-Probe Hyperpolarized 13C MRI for Improved Treatment and Therapeutic Monitoring

Award Number: R01CA215694
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY / ABSTRACT The goal of this image-guided drug delivery (IGDD) proposal is to overcome the translational barrier, as stated in PAR-16-044, to create a new quantitative imaging approach providing improved characterization of the cancer target for better drug selection and delivery, as well as improving real-time monitoring of whether the drug target was effectively treated. This will be accomplished by using a novel dual-probe (13C pyruvate and 13C glutamine) hyperpolarized (HP) 13C metabolic imaging technique to discriminate biologically divergent treatment-emergent neuroendocrine prostate cancer (NEPC) from advanced adenocarcinoma based on the metabolic profile of NEPC tumors and to use real-time changes in metabolism to monitor the drug's delivery and efficacy. NEPC is an increasingly prevalent, lethal subtype of prostate cancer that arises as an adaptive response to the application of androgen deprivation therapy and second-generation potent androgen pathway inhibitors. Neither blood tests (such as PSA or serum neuroendocrine markers) nor standard imaging metrics (like FDG PET) reliably distinguish NEPC from adenocarcinoma, nor quantify the degree of neuroendocrine differentiation. The scientific premise for this proposal is based on: (i) the success of our phase 1 clinical trial of HP 13C-pyruvate MRI in prostate cancer patients (7), (ii) the proliferation of commercially available clinical polarizers, (iii) the technical capability to image metastatic tumors, and (iv) the strong pre-clinical data demonstrating the value of HP 13C metabolic MRI in quantifying the MYC-mediated metabolic deregulation associated with neuroendocrine differentiation and in measuring its response to therapy. The clinical translation of this paradigm-shifting IGDD approach to improve the treatment of men with advanced prostate cancer is timely and meets a new important unmet clinical need. To accomplish this important project, we have assembled an exceptional team of basic science and clinical investigators with complimentary expertise in pre-clinical and clinical cancer research, HP 13C MRI, and in leading imaging and therapeutic clinical trials to: define the molecular and metabolic signature of NEPC tumors and develop new HP 13C labeled probes to identify neuroendocrine differentiation and treatment response (Aim 1); define the molecular and metabolic signature of metastatic NEPC tumors in patients and correlate with HP 13C pyruvate-to-lactate flux (kPL) measurements (Aim 2); perform first-ever serial combined HP 13C-pyruvate and HP 13C-glutamine MRI to investigate clinical value for distinguishing NEPC from adenocarcinoma and monitoring response to treatment (Aim 3). New research on the biology of NEPC has inspired novel investigational approaches to treating this disease, and although this proposal will focus on current standard of care treatment, the novel quantitative HP 13C metabolic MRI approaches developed in this proposal will have general applicability for a variety of new targeted therapeutic approaches being developed for NEPC including inhibitors of MYC transcriptional activity and glutamine metabolism.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	5	6/29/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $655,889 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	5	5/27/2021	NON-COMPETING CONTINUATION	$655,889
														Subtotal = $655,889

Issue Date FY: 2020 ( Subtotal = $655,889 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	4	5/13/2020	NON-COMPETING CONTINUATION	$655,889
														Subtotal = $655,889

Issue Date FY: 2019 ( Subtotal = $637,566 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	3	5/3/2019	NON-COMPETING CONTINUATION	$637,566
														Subtotal = $637,566

Issue Date FY: 2018 ( Subtotal = $656,096 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	2	4/25/2018	NON-COMPETING CONTINUATION	$656,096
														Subtotal = $656,096

Issue Date FY: 2017 ( Subtotal = $650,042 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Detection and Diagnosis Research	000	1	5/30/2017	NEW	$650,042
														Subtotal = $650,042

Grand Total All Awards = $3,255,482

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Targeting Neuroendocrine Prostate Cancer Using Multi-Probe Hyperpolarized 13C MRI for Improved Treatment and Therapeutic Monitoring

Award Number: R01CA215694

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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