Nuclear medicine is a clinical specialty that involves delivering radioactive substances to tumors for imaging and therapy. The most well-developed approach for radionuclide therapy is for neuroendocrine tumors and is attributed to the robust expression of somatostatin receptors (SSTR) on the surface of these lesions. Peptides that target SSTR have be conjugated to cell-killing radioisotopes in a technique known as peptide-receptor radionuclide therapy (PRRT). Although PRRT is the most effective treatment for metastatic neuroendocrine tumors, objective response rates are less than 20%. Combining PRRT with a chemotherapy agent has shown improved antitumor effects through radiosensitization, b...

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Nuclear medicine is a clinical specialty that involves delivering radioactive substances to tumors for imaging and therapy. The most well-developed approach for radionuclide therapy is for neuroendocrine tumors and is attributed to the robust expression of somatostatin receptors (SSTR) on the surface of these lesions. Peptides that target SSTR have be conjugated to cell-killing radioisotopes in a technique known as peptide-receptor radionuclide therapy (PRRT). Although PRRT is the most effective treatment for metastatic neuroendocrine tumors, objective response rates are less than 20%. Combining PRRT with a chemotherapy agent has shown improved antitumor effects through radiosensitization, but significant myelotoxicity has limited clinical utility.

The goal of this project is to safely deliver the radiosensitizer, temozolomide, to neuroendocrine tumors and increase the therapeutic effects of PRRT. Temozolomide is a DNA damaging agent that produces high responses rates in tumors when the DNA repair enzyme, known as MGMT, is inactivated. When given at high-doses, temozolomide therapy shuts down MGMT activity and its associated resistance mechanisms, rendering tumors more sensitive to treatment. We hypothesize that a tumor-targeted version of temozolomide could preferentially sensitize tumors to PRRT with low toxicity. We have used the clinical imaging agent, 68Ga-DOTA-TOC, as the model for tumor-targeted temozolomide and show strong preliminary evidence of targeting and efficacy.

In this proposal, we will test the ability of our agent to overcome resistance to MGMT and sensitize tumors to PRRT without damaging healthy organs. Successful completion of our aims would introduce a novel approach for tumor-targeted radiosensitization and could lead to higher PRRT response rates in patients who benefit from temozolomide therapy. Further impact may be in expanding radiosensitization to include carcinoid tumor patients who have intact MGMT and are resistant to temozolomide.

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