Targeting Mu Opioid Receptors in non-Small Cell Lung Cancer

University Of Missouri-Columbia, Columbia MO

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Abstract

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths worldwide. Patients have a dim prognosis with few treatment options. Thus, there is a critical need to develop molecular targets for lung cancer management. Compelling evidence indicates that mu (¿) opioid receptors regulate non-small cell lung cancer (non- SCLC) growth and metastasis. Immunoblotting studies show over-expression of ¿ opioid receptors by the major histological types of non-SCLC cell lines, and by multiple human non-SCLC tumor samples. Silencing the receptors, or ¿ opioid receptor antagonist blockade, inhibits non-SCLC growth and metastasis in vivo in animal models. These laboratory studies were prompted, in part, by clinical observations of longer than anticipated survival of certain cancer patients receiving the ¿ opioid receptor antagonist methylnaltrexone. We now propose to identify metabolically stable [111In]-labeled tetrapeptide radioligands for SPECT imaging that bind selectively, and with high affinity, to the peripheral ¿ opioid receptors expressed by non-SCLC tumors. We will be able to leverage off experience gained during the development of hydrophilic [111In]- labeled naltrindole analogs that bind tenaciously to peripheral ¿ opioid receptors, including those expressed by SCLC tumors in mouse models. Diagnostic PET imaging has allowed visualization of ¿ opioid receptors on the primary tumors of four of four non-SCLC patients. The study establishes sufficient site density for successful human imaging. However, current radioligands for ¿ opioid receptor PET were designed for brain imaging, and are unfavorable for oncology studies in the periphery because of high lipophilicity. Specific Aims are: 1) to prepare [111In]-labeled tetrapeptides that bind with high affinity and selectivity to ¿ opioid receptors; 2) to characteriz opioid receptor binding in non-SCLC cells and tumor membranes using known [3H]-labeled radioligands (¿, ¿, ?), as well as the novel [111In]-labeled ¿ opioid receptor tetrapeptides; and 3 to evaluate the pharmacokinetics, pharmacology, stability and SPECT imaging potential of the novel [111In]-labeled tetrapeptides in vivo in normal mouse, and in SCID mouse models of non-SCLC. Radioligands optimized for diagnostic SPECT studies of peripheral ¿ opioid receptors would be candidates for clinical translation. They have potential for stratification of non-SCLC patients into a cohort that might benefit from the emerging ¿ opioid receptor antagonist therapies.