A therapeutic approach for potential prevention of aromatase inhibitor-induced bone loss

AbstractIn this SBIR Phase I applicationour goal is to demonstrate proof of concept of our lead chelating agent as a potential therapeutic for the prevention of osteoporosis induced by aromatase inhibitorAItherapy in postmenopausal women with hormone receptor positive breast cancerAlthough AI therapy shows great improvements in cancer free and overall survivalits treated patients face a risk of osteoporosisbecause AI inhibits estrogen generationIn factAI skeletal toxicity has become the most frequent reason for AI therapy discontinuationCurrentlythere are very few therapeutic options for preventing AI induced osteoporosisBisphosphonates and denosumabtwo popular osteoporotic drugsare protectivehowever both have an untreatable side effectosteonecrosis of the jawas well as other concerns regarding toxicity and inadequate therapeutic efficacyHerewe hypothesize that AI induced osteoporosis may be prevented by our chelating agent without adverse effects on AI actionsthis agent is able to target new osteoporotic pathogenshence having potential as a better alternative to current osteoporotic drugs for AI treated breast cancer patientsThis hypothesis is supported by our studies that show the ability of our chelating agent to prevent bone loss in ovariectomizedOVXratsa postmenopausal osteoporotic model due to estrogen deficiencyIt is reasonable to exploit this finding toward the development of new drugs for treating AI induced osteoporosisdue to the similarities of the OVX and AI mechanisms of actions in causing estrogen deficiency and consequent bone lossTwo US patents on this technology have been licensed to NanoMedica University of UtahUUstartup company which has been broadening the technology application and seeking additional patent protectionOur aim is to synthesize the lead agent and define its efficacy for preventing osteopenic development in AI treated OVX ratsSpecificallyafter synthesisthe agent will be evaluated in AI treated OVX ratsand compared with rats that are sham OVXOVXand OVX treated with AI or AI bisphosphonateA dose response study will be conducted to further confirm the therapeutic efficacyCollected bone samplese gfemurtibia and vertebrawill be examined for treatment effectiveness using histomorphometric methods and various imaging technologiesBlood samples will also be tested for estrogen levels to determine whether the agent has any adverse effects on AI treatmentand for serum bone biomarkers in order to evaluate the agentandapos s efficacyAll of these types of experimental procedures have been performed in our labTo our best knowledgeour lab is the only one to develop a new kind of chelation therapeutic approach for AI induced bone lossOur team possesses multidisciplinary expertise in chelating drug discoverybone biologyand bone therapeutic evaluationWe believe that this Phase I study will succeedand lay the foundation for the following Phase II studyto fulfill an investigational new drug submission to the FDAUltimatelyour development will bring neweffective osteoporotic adjuvant drugs to the global market NarrativeThere is an urgent and unmet need for the development of alternative drugs for aromatase inhibitorAIinduced osteoporosis in postmenopausal women with hormone receptor positive breast cancer because the current osteoporotic medicinessuch as bisphosphonate and denosumabhave shown serious side effects and inadequate therapeutic effectivenessOur prior studies have found that the chelating agents developed in our lab have a new mechanism of action which can effectively prevent bone loss by depleting excess skeletal ironmitigating bone oxidative damage associated with such iron in ovariectomized ratsa standard animal model for postmenopausal osteoporosis due to estrogen deficiencyIn this proposed projectwe will exploit this finding to develop our chelating agents into safermore effective osteoporotic drugs with potential to be alternatives to bisphosphonate and denosumab in treating breast cancer patients who undergo AI therapyBased on our promising studieswe believe that this proposed investigation could lead to the discovery of new chelating therapeutics for AI induced osteoporosisthus significantly impacting the clinical management of breast cancer patients undergoing AI therapy