Breast cancer is the most frequent malignant tumor of women of all races in North America and is the second leading cause of death among women (DHHS, CDC, & NCI; 2014) with an overall NIH estimate costs to the U.S. over $200 billion with $88.7 billion in direct medical costs in 2011. The World Health Organization predicts that global cases of cancer will rise to 15 million new cases by 2020. In advanced stages, skeletal metastasis causes incapacitating pain and is prominent in 75?90% of cancer patients. First line therapy to treat bone cancer pain includes mu opioid receptor agonists. Opioids are well known for producing unwanted side effects in cancer patients including severe somnolence, constipation, etc. but recently have been shown (clinical and preclinical) to enhance the risk of bone loss and fracture. In addition, sustained opioids have demonstrated a propensity for increasing proliferation and migration of different cancers including breast cancer. Data from our laboratory, and others, suggest that cannabinoid CB2 agonists may be effective in alleviating bone cancer pain and bone loss. Selective CB2 agonists significantly inhibit bone cancer pain while NOT resulting in the psychotropic or euphoric effects seen with CB1 agonists or narcotics. Recent reports and data from our lab have identified CB2 agonists as significantly reducing self-administration of drugs of abuse including cocaine and narcotics. Increasing endogenous cannabinoids (MAGL inhibition to increase 2- arachidonylglycerol - 2AG) may regulate bone mass, decrease pro-nociceptive factors and act synergistically with morphine to inhibit cancer-induced bone pain (CIBP) and attenuate tumor proliferation. Our preliminary studies using a murine bone cancer model indicate that MAGL inhibition and CB2 receptor activation inhibits proinflammatory cytokines/chemokines via regulating NF-?B. Yet, there is very little known about the endogenous CB2 system in bone cancer pain/inflammation, and whether the activation of the endocannabinoid (eCB) system, while administering mu opioids, will significantly aid bone cancer patients. There are NO studies investigating the synergistic combination of MAGL inhibitor or CB2 agonists with a mu opioid agonist on cancer pain, bone integrity, tumor proliferation, or attenuating mu opioid unwanted side effects. Our progress in characterizing bone cancer pain has resulted in twelve direct peer-reviewed publications and preliminary data to further support studies of MAGL inhibition, CB2 receptor activation in bone cancer pain. Our preliminary data demonstrate; 1) a reproducible syngeneic breast-induced bone cancer model representative of the clinical state, 2) MAGLipase inhibition resulting in increased 2AG, significantly attenuating cancer-induced pain, 3) exogenous and endogenous CB2 agonists attenuating bone loss, 4) sustained morphine alone increases bone degradation and cytokines, 5) CB2 agonists and MAGL inhibitors decrease NF-kB signaling, inhibiting several pro-inflammatory cytokines/chemokines, while reinstating apoptosis in breast cancer cells, 6) synergistic inhibition of CIBP with morphine and CB2 agonists, and 7) CB2 agonists lacking unwanted side effects. Hence, MAGLipase inhibitors in combination with morphine may be synergistic in alleviating bone cancer pain, attenuate breast cancer proliferation while maintaining bone mass. In response to the recent call for proposals (RFA PA-15-188) titled ?Developing the Therapeutic Potential of the Endocannabinoid System for Pain Treatment? and our preliminary findings have led us to hypothesize that MAGLipase inhibition and/or CB2 receptor activation, in combination with a Mu opioid agonist will result in the synergistic inhibition of pain behaviors in a murine model of breast-induced bone cancer pain while attenuating bone loss seen with opioids. Mechanistically, 2AG and CB2 agonists act via the CB2 receptor to inhibit a common transcription factor, NF-?B, regulating multiple cytokines/chemokines. We propose to use behavioral, biochemical, immune and molecular strategies to test whether MAGL inhibition and/or CB2 agonist, in the presence of morphine (standard clinical care) will be a beneficial therapy for breast-induced bone cancer pain. This hypothesis will be tested by the following Aims using our syngeneic (non-immune-compromised) murine model of CIBP:
Aim 1. Determine whether the inhibition of MAGLipase attenuates breast cancer-induced bone pain and/or alter bone resorption and remodeling.
Aim 2. Explore whether MAGLipase inhibition and CB2 receptor activation attenuates breast cancer-induced bone pain by inhibiting pronociceptive cytokines/chemokines via a common transcription factor.
Aim 3. Determine whether a MAGL inhibitor and the activation of the CB2 and Mu opioid receptors result in the synergistic inhibition of breast cancer-induced bone pain while reducing bone loss. These studies will lead to urgently needed new treatments and may likely apply to other metastatic cancers, including lung and prostate.

Public Health Relevance

Breast cancer is the most frequent malignant tumor of women of all races in North America and is the second leading cause of death among women (DHHS, CDC, & NCI; 2014). In advanced stages, skeletal metastasis causes incapacitating pain and is prominent in 75?90% of cancer patients. First line therapy to treat bone cancer pain includes mu opioid receptor agonists. Recent studies in humans demonstrated a significant increase in risk of bone fracture increases in proliferation/migration of tumors in users of sustained opiates. This proposal addresses the use of a MAGL inhibitor in order to increase levels of endogenous 2AG while at the same time reducing the endogenous eicosanoids (i.e., prostaglandins) in a murine model of breast-induced bone cancer. Our preliminary data suggest that such treatments will significantly decease the deleterious effects of the tumor as well as sustained morphine by inhibiting a common cytokine/chemokine transcription factor.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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St Germain, Diane
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University of Arizona
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Zhang, Hong; Lund, Dominique M; Ciccone, Haley A et al. (2018) Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. Pain 159:1814-1823
Grenald, Shaness A; Doyle, Timothy M; Zhang, Hong et al. (2017) Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation. Pain 158:1733-1742
Grenald, Shaness A; Young, Madison A; Wang, Yue et al. (2017) Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. Neuropharmacology 116:59-70
Slosky, Lauren M; BassiriRad, Neemah M; Symons, Ashley M et al. (2016) The cystine/glutamate antiporter system xc- drives breast tumor cell glutamate release and cancer-induced bone pain. Pain 157:2605-2616
Forte, Brittany L; Slosky, Lauren M; Zhang, Hong et al. (2016) Angiotensin-(1-7)/Mas receptor as an antinociceptive agent in cancer-induced bone pain. Pain 157:2709-2721
Hanlon, Katherine E; Lozano-Ondoua, Alysia N; Umaretiya, Puja J et al. (2016) Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent. Breast Cancer (Dove Med Press) 8:59-71
Slosky, Lauren M; Largent-Milnes, Tally M; Vanderah, Todd W (2015) Use of Animal Models in Understanding Cancer-induced Bone Pain. Cancer Growth Metastasis 8:47-62
Lozano-Ondoua, A N; Symons-Liguori, A M; Vanderah, T W (2013) Cancer-induced bone pain: Mechanisms and models. Neurosci Lett 557 Pt A:52-9
Lozano-Ondoua, Alysia N; Hanlon, Katherine E; Symons-Liguori, Ashley M et al. (2013) Disease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists. J Bone Miner Res 28:92-107
Lozano-Ondoua, Alysia N; Wright, Courtney; Vardanyan, Anna et al. (2010) A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss. Life Sci 86:646-53

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