Prostate cancer is unique among cancers as although it is highly metastatic, bone is frequently the only clinically detectable site of metastasis. Fortunately, patients with metastatic prostate cancer usually have a long survival time. Unfortunately, prostate metastasis to bone frequently causes a severe, chronic pain that reduces quality of life, functional status, and greatly increases health care utilization. The goals of this application are to understand the mechanisms that drive prostate cancer-induced bone pain and use this information to develop therapies that can better prevent and/or treat this chronic pain. In preliminary studies, we have refined a mouse model of prostate cancer bone pain so that it closely mirrors many of the pathological features observed in humans with prostate metastasis to bone in terms of: the tumor being primarily osteoblastic, the pattern of tumor colonization in bone, the individual tumor colonies forming sclerotic bone lesions, the robust vascularization, and viability of the tumor. While these prostate cancer cells do not express nerve growth factor (NGF), preliminary data suggest their associated stromal cells release NGF that induces dramatic sprouting of tropomyosin receptor kinase A (TrkA)+ sensory and sympathetic nerve fibers in the tumor-bearing bone that may play a major role in driving chronic prostate cancer-induced bone pain. Based on these observations, we hypothesize that: (1) NGF released from specific populations of stromal cells induces marked sprouting and neuroma formation by TrkA+, but not TrkA-, sensory and sympathetic nerve fibers in the tumor-bearing bone and that the extent of this pathological reorganization will predict the severity of prostate-induced pain behaviors;(2) newly sprouted sensory and sympathetic nerve fibers have a distinct morphology and express pathologically high levels of pro-algesic neurotransmitters, channels/receptors, and mitogen-activated protein kinases that are never observed in nerve fibers that innervate the normal bone;and (3) early preventive administration of anti-NGF or anti-TrkA attenuates the tumor-induced nerve sprouting, the pro-algesic phenotype of sensory and sympathetic nerve fibers, and bone cancer pain. In contrast, late administration of anti-NGF or anti-TrkA will only partially reverse the pro-algesic phenotype of the nerve fibers and have little or no effect on the pathological sprouting or neuroma formation that has already occurred. The overarching hypothesis is that the earlier preventive blockade of the NGF/TrkA pathway is initiated, the more effectively the pathological nerve changes and pain can be controlled. If correct, data from this project may fundamentally change our understanding and treatment of prostate cancer-induced bone pain.

Public Health Relevance

Prostate cancer is unique among cancers as although it is spreads to different organs, bone is frequently the only clinically detectable site of metastasis. Fortunately, patients with metastatic prostate cancer usually have a long survival time. Unfortunately, prostate metastasis to bone frequently causes a severe, chronic pain that reduces quality of life, functional status and greatly increases health care utilization. The goals of this application are to understand the mechanisms that drive prostate cancer-induced bone pain and to use this information to develop therapies that can better treat this chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA157449-02
Application #
8287533
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
O'Mara, Ann M
Project Start
2011-07-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$314,363
Indirect Cost
$106,863
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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