Principal Investigator

Todd W
Awardee Organization

University Of Arizona
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Cannabinoid CB2 Agonists for Treatment of Breast Cancer Induced Bone Pain

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 2arachidonylglycerol - 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-κB. 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-κB, 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.


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  • Zhang H, Largent-Milnes TM, Vanderah TW. Glial neuroimmune signaling in opioid reward. Brain research bulletin. 2020 Feb;155:102-111. Epub 2019 Nov 29. PMID: 31790721
  • Slosky LM, BassiriRad NM, Symons AM, Thompson M, Doyle T, Forte BL, Staatz WD, Bui L, Neumann WL, Mantyh PW, Salvemini D, Largent-Milnes TM, Vanderah TW. The cystine/glutamate antiporter system xc- drives breast tumor cell glutamate release and cancer-induced bone pain. Pain. 2016 Nov;157(11):2605-2616. PMID: 27482630
  • Thompson AL, Largent-Milnes TM, Vanderah TW. Animal Models for the Study of Bone-Derived Pain. Methods in molecular biology (Clifton, N.J.). 2019;1914:391-407. PMID: 30729479
  • Zhang H, Lund DM, Ciccone HA, Staatz WD, Ibrahim MM, Largent-Milnes TM, Seltzman HH, Spigelman I, Vanderah TW. Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. Pain. 2018 Sep;159(9):1814-1823. PMID: 29781960
  • Grenald SA, Young MA, Wang Y, Ossipov MH, Ibrahim MM, Largent-Milnes TM, Vanderah TW. Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. Neuropharmacology. 2017 Apr;116:59-70. Epub 2016 Dec 20. PMID: 28007501
  • Wiese BM, Liktor-Busa E, Levine A, Couture SA, Nikas SP, Ji L, Liu Y, Mackie K, Makriyannis A, Largent-Milnes TM, Vanderah TW. Cannabinoid-2 Agonism with AM2301 Mitigates Morphine-Induced Respiratory Depression. Cannabis and cannabinoid research. 2021 Oct;6(5):401-412. Epub 2020 Nov 13. PMID: 33998869
  • Sulaiman MI, Alabsi W, Szabo L, Hay M, Polt R, Largent-Milnes TM, Vanderah TW. PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease. International journal of molecular sciences. 2023 Oct 9;24. (19). PMID: 37834455
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  • Forte BL, Slosky LM, Zhang H, Arnold MR, Staatz WD, Hay M, Largent-Milnes TM, Vanderah TW. Angiotensin-(1-7)/Mas receptor as an antinociceptive agent in cancer-induced bone pain. Pain. 2016 Dec;157(12):2709-2721. PMID: 27541850
  • Hanlon KE, Lozano-Ondoua AN, Umaretiya PJ, Symons-Liguori AM, Chandramouli A, Moy JK, Kwass WK, Mantyh PW, Nelson MA, Vanderah TW. Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent. Breast cancer (Dove Medical Press). 2016 Apr 15;8:59-71. doi: 10.2147/BCTT.S100393. eCollection 2016. PMID: 27186076
  • François-Moutal L, Wang Y, Moutal A, Cottier KE, Melemedjian OK, Yang X, Wang Y, Ju W, Largent-Milnes TM, Khanna M, Vanderah TW, Khanna R. A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors. Pain. 2015 Jul;156(7):1247-1264. PMID: 25782368
  • Wiese BM, Liktor-Busa E, Couture SA, Nikas SP, Ji L, Liu Y, Makriyannis A, Spigelman I, Vanderah TW, Largent-Milnes TM. Brain Penetrant, but not Peripherally Restricted, Synthetic Cannabinoid 1 Receptor Agonists Promote Morphine-Mediated Respiratory Depression. Cannabis and cannabinoid research. 2022 Oct;7(5):621-627. Epub 2021 Dec 17. PMID: 34935460
  • Lozano-Ondoua AN, Wright C, Vardanyan A, King T, Largent-Milnes TM, Nelson M, Jimenez-Andrade JM, Mantyh PW, Vanderah TW. A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss. Life sciences. 2010 Apr 24;86(17-18):646-53. Epub 2010 Feb 20. PMID: 20176037
  • Ellingson HM, Vanderah TW. Potential therapeutic treatments of cancer-induced bone pain. Current opinion in supportive and palliative care. 2020 Jun;14(2):107-111. PMID: 32349095
  • Lozano-Ondoua AN, Symons-Liguori AM, Vanderah TW. Cancer-induced bone pain: Mechanisms and models. Neuroscience letters. 2013 Dec 17;557 Pt A(0 0):52-9. Epub 2013 Sep 25. PMID: 24076008
  • Grenald SA, Doyle TM, Zhang H, Slosky LM, Chen Z, Largent-Milnes TM, Spiegel S, Vanderah TW, Salvemini D. Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation. Pain. 2017 Sep;158(9):1733-1742. PMID: 28570482
  • Thompson AL, Grenald SA, Ciccone HA, Mohty D, Smith AF, Coleman DL, Bahramnejad E, De Leon E, Kasper-Conella L, Uhrlab JL, Margolis DS, Salvemini D, Largent-Milnes TM, Vanderah TW. Morphine-induced osteolysis and hypersensitivity is mediated through toll-like receptor-4 in a murine model of metastatic breast cancer. Pain. 2023 Nov 1;164(11):2463-2476. Epub 2023 Jun 15. PMID: 37326644
  • Lozano-Ondoua AN, Hanlon KE, Symons-Liguori AM, Largent-Milnes TM, Havelin JJ, Ferland HL 3rd, Chandramouli A, Owusu-Ankomah M, Nikolich-Zugich T, Bloom AP, Jimenez-Andrade JM, King T, Porreca F, Nelson MA, Mantyh PW, Vanderah TW. Disease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2013 Jan;28(1):92-107. PMID: 22903605
  • Slosky LM, Largent-Milnes TM, Vanderah TW. Use of Animal Models in Understanding Cancer-induced Bone Pain. Cancer growth and metastasis. 2015 Aug 23;8(Suppl 1):47-62. doi: 10.4137/CGM.S21215. eCollection 2015. PMID: 26339191
  • Thompson AL, Grenald SA, Ciccone HA, BassiriRad N, Niphakis MJ, Cravatt BF, Largent-Milnes TM, Vanderah TW. The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain. The Journal of pharmacology and experimental therapeutics. 2020 May;373(2):230-238. Epub 2020 Feb 13. PMID: 32054717