Designer therapy of pancreatic tumors

Problem:Pancreatic cancer is the fourth leading cause of cancer-relateddeath in men and women with an overall 5% 5 year survival,underscoring the need for novel multimodality treatmentapproaches. Although pancreatic cancer is often treatable whencaught in the early stages, the vast majority of cases arediagnosed in the late stages. There are no reliable screeningmethodologies for early diagnosis and symptoms are oftenvague and easily confused with other diseases. For localizedcancers, surgical resection remains the cornerstone oftreatment in only 15-20% of patients, however local and distantfailure rates are often high with only 3-4% of patients achievinglong-term control and cure. Various strategies in the form ofneoadjuvant and adjuvant treatment and radiotherapy havebeen employed over the years to improve outcome, with limitedsuccess and undesirable side-effects. A combinedchemoradiation approach may improve postoperative survivaloutcome by optimizing local tumor control and surgicalresect ability. A therapy that selectively targets tumor cells whilemaintaining low systemic toxicity is warranted.Technology:This technology encompasses five substituted deoxycytidine prodrug analogs, which require deamination foractivation. In tumors expressing high levels of cytidine deaminase such as pancreatic tumors, these agents can beactivated for tumor targeted therapy without systemic toxicity. Combining these agents with modulatory doses ofcytidine deaminase inhibitors increases tumor selectivity and growth inhibition. Once this composition isincorporated into tumor cell DNA, it can be converted to a radiosensitizing agent in tumors via thymidine kinase fortumor-targeted chemoradiation. This therapy overcomes the commonly associated chemotherapeutic resistance ofcytidine analogues used for treatment of pancreatic cancer such as Gemcitabine, which occurs in response to hightumor cytidine deaminase expression/activity. Suraj Kachgal sxk1350@med.miami.edu (305) 243-3447