Daniel E. Frigo
Cancer Systems Imaging
Areas of Research
- Prostate Cancer
- Molecular Biology
- Drug Development
- Cancer Metabolism
The Frigo Laboratory aims to identify and therapeutically target novel signaling pathways in prostate cancer. The lab is currently focused on understanding how various signaling pathways — such as those regulated by the androgen receptor, CAMKK2, AMPK, mTOR and MYC — drive the progression of prostate cancer. The long-term goal of this work is to exploit these newly uncovered pathways for therapeutic purposes. Interestingly, many of these signaling pathways converge at various metabolic nodes. The end result is a shift in oncogenic metabolism that allows the cancer cells to utilize a diverse array of nutrients to the benefit of the cancer cell.
Goals of the Frigo Lab
- Identify the signaling pathways that promote prostate cancer progression
- Delineate the regulation and role of diverse signaling networks in cancer metabolism
- Leverage novel imaging techniques to study subcellular signaling events and cancer metabolism
- Develop new therapeutic approaches for the treatment of advanced prostate cancer
Steroid hormones are chemicals that are made in one part of our body and can travel great distances to signal specific events in other parts of our body. At the molecular level, steroid hormones communicate by binding to and activating a class of proteins known as nuclear receptors. These hormone-bound receptors can then turn on or off various cellular signaling pathways that collectively control different biological responses. For example, androgens, such as testosterone, are male sex steroid hormones that are produced mainly in the testes and can circulate through our bloodstream to various targets like the prostate where the hormone promotes the normal development of this organ by binding to and activating androgen receptors (ARs). Importantly, while androgens are required for males to develop normally, abnormal androgen signaling can promote prostate cancer.
Despite the known importance of androgens in prostate cancer, it is still unclear which of the hundreds to thousands of androgen-regulated signaling pathways are responsible for causing the progression of the disease. Moreover, it is now clear that there are new prostate cancer subtypes emerging as the result of next-generation AR-targeting drugs. These new cancer subtypes are androgen-indifferent and likely driven by unique mechanisms that need to be defined. To address this knowledge gap, my laboratory takes a multidisciplinary approach that encompasses fields spanning from genomics to pharmacology to biochemistry to molecular and cellular biology, testing in preclinical animal models of prostate cancer, as well as the development of new clinical trials. This approach facilitates the identification of those pathways that are actually driving the stages of the disease for which patients have limited treatment options. Most recently, we have been heavily focused on understanding how these pathways alter cellular metabolism to promote disease progression. Now, we are also positioned to then rapidly test whether these newly identified metabolic pathways represent realistic therapeutic targets and hence, set the foundation for developing mechanistically innovative drugs.
Current Research Grants and Awards
R01 CA275138 (Frigo, Zurita) 05/12/23–04/30/28
Revisiting Antiangiogenic Therapy to Target Hormone-Sensitive Prostate Cancer Metabolism
The goals of this proposal are to 1) test if targeting central carbon metabolism can sensitize hormone-sensitive prostate cancers to inhibitors of angiogenesis and 2) evaluate if biomarkers of metabolic signaling can predict response to antiangiogenic therapy.
Role: Lead/Contact PI
R01CA283402 (Aparicio, Frigo, Sharma) 09/21/23–08/31/28
Effects of Arginine Depletion Combined with Platinum-Taxane Chemotherapy in Aggressive Variant Prostate Cancers (AVPC)
The goals of this proposal are to 1) determine the safety and efficacy of ADI-PEG20 combined with carboplatin+cabazitaxel chemotherapy (ADI-CC) in men with AVPC in a Phase 2 clinical trial, 2) determine the effects of ADI-CC on arginine metabolism and associated pathways in the AVPC tumor microenvironment, and their association with outcomes and, 3) determine the effects of ADI-CC on immune-cell populations and checkpoint expression in the AVPC tumor microenvironment.
HT9425-23-1-0424 (Frigo) 05/15/23–05/14/26
DoD/PCRP Idea Development Award
Targeting Serine and One-Carbon Metabolism for the Treatment of Aggressive Variant Prostate Cancer
The goals of this proposal are to understand how the loss of RB leads to increased serine and one-carbon metabolism, what it uses this metabolic pathway for, and evaluate whether serine/glycine-deprivation represents a viable treatment option for RB-deficient AVPC.
W81XWH-22-1-0686 (Frigo) 09/01/22–08/31/25
DoD/PCRP Idea Development Award
Disrupting Access to Intracellular Lipid Depots to Treat Advanced Prostate Cancer
The goals of this proposal are to evaluate whether intracellular lipolysis represents a viable therapeutic target for the treatment of advanced prostate cancer and understand how lipolysis promotes disease progression.
Prostate Cancer Moon Shot (Aparicio, Logothetis, Navin) 09/01/23–08/31/24
University of Texas MD Anderson Moon Shots Program
Linking One-Carbon Metabolism to Lineage Promiscuity in Aggressive Variant Prostate Cancers
The goal of this study is to determine how perturbations of the metabolic milieu impact lineage promiscuity in AVPC tumors and subsequent response to therapy.
Role: Priority Project 3 Co-PI (Co-PIs: Frigo, Aparicio, Wang, Soundararajan, Estecio, Lu)
Foundation Grant (Frigo, Aparicio) 01/01/23–12/31/23
The Mike Slive Foundation
Targeting Arginine Metabolism to Treat Aggressive Variant Prostate Cancers
The goal of this study test if depleting arginine levels can impair the growth of a highly aggressive subset of prostate cancers.
Role: lead/contact PI
W81XWH-22-1-0187/8 (Frigo, Zurita) 09/01/22–08/31/25
DoD/PCRP Translational Science Award
Revisiting Antiangiogenic Therapy to Target Prostate Cancer Metabolism
The goal of this proposal is to evaluate whether co-targeting cancer cell anaplerotic metabolism and angiogenesis can synergize to treat advanced prostate cancer. In addition, we seek to determine whether biomarkers of anaplerotic signaling can predict response to antiangiogenic therapy and therefore, guide patient selection.
Role: lead/contact PI
R03 CA270450 (Frigo) 04/01/22–02/29/24
Delineation of the Role of CAMKK2 in Bone-metastatic Prostate Cancer and its Therapeutic Implications
The goal of this proposal is to define CAMKK2’s role in prostate cancer bone metastasis and associated bone disease. These findings will help drive the development of new CAMKK2-targeted therapies and can inform future clinical trials. Moreover, we anticipate that CAMKK2 inhibition may also improve the safety and efficacy of existing treatments.
RSG-20-138-01 - TBE (Delk) 02/01/21–01/31/25
American Cancer Society/University of Texas-Dallas
IL-1-p62 Axis Regulation and Function in Castration Resistant PCa
The goal of this subcontract is to perform orthotopic xenograft injections of parental IL-1 sublines in castrated and enzalutamide-treated mice given verteporfin and monitor tumor growth and metastasis to support the parent project at The University of Texas – Dallas.
Role: Collaborator/Subcontract PI
Quantitative Imaging Analysis Core (QIAC) Pilot Grant (Frigo, Klekers) 06/1/22–04/30/24
University of Texas MD Anderson Cancer Center
Evaluation of 11C-choline PET as a biomarker for ATGL-driven prostate cancer metabolism
The goal of this pilot project is to test if existing PET imaging agents can be used as a biomarker of ATGL activity.
R01 CA184208 (Frigo) 1/27/15–12/31/19
Genetic & Metabolic Dissection of the CAMKKbeta Signaling Axis in Prostate Cancer
The goal of this project is to use a combination of in vitro and in vivo models to define the specific role(s) of AR-mediated CaMKKb signaling in prostate cancer and test whether it represents a viable drug target in preclinical animal models.
RSG-16-084-01 - TBE (Frigo) 7/1/16–6/30/20
American Cancer Society
Therapeutic Targeting of Autophagy in Prostate Cancer
The goal of this project is to define the specific role(s) of androgen receptor-mediated autophagy in prostate cancer and test whether is represents a viable drug target in preclinical animal models.
R21 CA191009 (Frigo) 2/1/15–1/31/17
Androgen Receptor- and Myc-Mediated Glutamine Metabolism in Prostate Cancer
The goal of this proposal is to use a combination of preclinical models to understand the relationship between AR signaling and glutamine metabolism to determine whether their intersection represents a viable therapeutic target.
U24DK100469 (Sreekumaran) 5/21/14–8/31/15
Metabolic Dissection of Aberrant Glutamine Metabolism in Prostate Cancer
The goal of this pilot grant sponsored through the Mayo Clinic Metabolomics Resource Core (MCMRC) Pilot and Feasibility Program is to leverage the existing strengths MCMRC to understand the relationship(s) between AR signaling and glutamine metabolism using stable isotope metabolic flux analyses.
Role: Subaward PI
W81XWH-12-1-0204 (Frigo) 6/1/12–5/31/15
The CaMKK beta-AMPK Signaling Axis as a Biomarker and Therapeutic Target for Advanced Prostate Cancer
The primary goal of this proposal is to use a combination of molecular biology and preclinical models to define the specific role(s) of the CaMKKb-AMPK signaling axis in prostate cancer.