DTP serves as a major link for t he translation of therapeutic concepts emerging from the laboratories of the KCC to clinical application and, develops therapeutic approaches based on laboratory and/or preliminary clinical research done at the KCC or elsewhere. The capabilities of the DTP members include molecular target identification of potential therapeutic utility, computer-generated molecular modeling of potential therapeutic agents based on target configuration, synthesis of candidate agents, in vitro and in vivo pre-clinical screening. Phase3 I and II clinical trials with pharmacokinetic/pharmacodynamic correlations, as well as biologic correlations, as well as biologic correlations in early clinical trials so as to optimize the clinical use of new agents or combinations. The DTP is organized as 6 working groups which include multi- disciplinary pre-clinical and clinical investigators. 1) Antisense vs. IGF- 1R. Laboratory and initial phase I clinical testing of phosphorotiate oligonucleotide vs. IGF-1R has shown dramatic antitumor (apoptotic) efficacy with an excellent safety profile. RAID grant support has facilitated GMP synthesis for further clinical testing. 2) Vaccine vs. mutant EGFRvIII: Laboratory studies have shown effective immunization against tumors that express the mutant EGFvIII receptor, especially breast cancer. RAID grant support has facilitated GMP synthesis for further clinical testing. 2) Vaccine vs. mutant EGFRvIII: Laboratory studies have shown effective immunization against tumors that express the mutant EGFvIII receptor, especially breast cancer. RAID funding has allowed GMP synthesis of the peptide vaccine for initial Phase I clinical trial. 3) Anti-angiogenesis: Phase I clinical testing with pharmacokinetic and pharmacodynamic assessments with Angiostatin is under way.
The aim of these studies will determine the safety and the optimal biological dose using assessments of tumor blood flow and angiogenic factors with the aid of invasive and non-invasive techniques. Similar studies are planned using humanized monoclonal antibodies against alphavbeta3 integrin. 4) Antisense vs. ERB-B2 and K-RAS phosphorothioate antisense oligonucleotides vs. ERB-B2 and K-RAS have shown efficacy against several human tumors, most notably ovarian cancers. 5) FHIT gene therapy: Investigators at the KCC discovered the FHIT gene, a tumor suppressor gene, found to be commonly deleted in a high frequency of pre-neoplastic and frankly neoplastic conditions. In the laboratory, transfection of the FHIT gene into cell cells in vitro leads to tumor cell apoptosis In vivo studies produce similar apoptotic effects without apparent toxicity to normal organs. Current efforts are directed to the development of appropriate viral vectors that would result in high levels of FHIT gene transfection rates. 6) Development of small molecule inhibitors of Bcl22: The anti-apoptotic Bcl2 gene is over-expressed in many malignancies. This over-expression has been related to poor prognosis and resistance to cytotoxic therapies. Peptidic and small molecule non-peptidic inhibitors of Bcl-2 have been developed. For the implementation of the translational research/clinical trials the members of the DTP have established collaborative relationships with other programs of the KCC and physicians in the Jefferson Cancer Network.
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