Revisiting Antiangiogenic Therapy to Target Prostate Cancer Metabolism
Abstract
Rationale: Cancers are much like new subdivisions in that they both require a constant supply of building blocks as well as energy to assemble these building blocks into new structures, such as a growing tumor in the case of cancer or a series of new buildings in the case of a subdivision. Nutrients in our blood provide cancers with the necessary building blocks they need for both growth and energy. Because cancers need a constant source of nutrients, they will create new blood vessels that essentially feed the tumor, a process called angiogenesis. Due to the importance of this process, inhibitors of angiogenesis were developed and are routinely used for the treatment of a number of cancer types, but not prostate cancer. Despite the known importance of angiogenesis in advanced prostate cancer and clear signs that angiogenesis inhibitors can impair prostate cancer growth in some men, large clinical trials testing these angiogenesis inhibitors failed to demonstrate improved overall survival. However, those trials did not incorporate any criteria or markers to help select the prostate cancer patients most likely to benefit from the angiogenesis inhibitors being tested. Another hallmark of cancers is their ability to take up and break down (metabolize) diverse nutrients to satisfy their need for building blocks and energy. One of the most important metabolic pathways in cells is the tricarboxylic acid (TCA) cycle. In addition to providing energy for the cell, the TCA cycle provides precursors for various metabolic processes. Rapidly dividing cells, such as cancer cells, constantly deplete and then need to replenish this central metabolic hub via a process known as anaplerosis. Not surprisingly, pro-cancer signaling can increase cellular anaplerosis. Conversely, blocking anaplerosis places considerable toxic stress on tumor cells. Preliminary data indicate that blockade of anaplerotic signaling pathways in advanced prostate cancers, while initially able to slow tumor growth, invariably gives way to resistant tumors. Interestingly, a common feature of these relapsed tumors is increased angiogenesis. Interrogation of patient-derived tumor specimens indicates that there exists a compensatory correlation between angiogenesis and anaplerotic signaling pathways, suggesting that, when one process is low, the other needs to be high to sustain the tumor’s metabolic demands. Objectives: The primary objectives of this study are to test whether novel combination therapies targeting anaplerosis and angiogenesis can improve prostate cancer responsiveness to either agent alone. We predict that the levels of anaplerotic stress induced by this approach will correlate with therapeutic benefit. To further clarify this relationship, we will leverage two completed clinical trials in men presenting with aggressive prostate cancer to determine whether markers of anaplerotic signaling and/or stress can help predict response to antiangiogenic therapy and therefore guide patient selection for future clinical trials. Aims: Aim 1 will test whether angiogenesis inhibitors can sensitize mouse models of advanced prostate cancer to the inhibition of CAMKK2 signaling, an androgen-regulated pathway and emerging therapeutic target that promotes anaplerotic metabolism of glucose. We will also determine whether the degree of anaplerotic stress caused by angiogenesis inhibitors can predict which tumors will respond best to CAMKK2 inhibition. Although clinical-grade CAMKK2 inhibitors are not yet available, drug development is in progress. In Aim 2, we will take a different approach to block anaplerosis by using inhibitors of glutamine metabolism that are currently in clinical trials. Use of these metabolic inhibitors in combination with FDA-approved antiangiogenic agents will not only test a clinically viable treatment combination, but will also serve to further validate our broader mechanistic hypothesis that co-targeting angiogenes
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210188
Entities
People
- Amado Zurita
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army