Malignant gliomas represent the largest group of glial tumors, and they have a poor prognosis because of their high proliferation potential, strong tendency for intracranial dissemination, and the severe adverse effects of conventional therapies. Although surgical resection with adjuvant chemotherapy and/or radiotherapy is used to treat malignant gliomas, inherent tumor resistance to radiation or chemotherapy and toxicity from systemic administration of antineoplastic agents often hinders a successful outcome. Therefore, motivated by the limitations of current therapeutic approaches for gliomas, our long term goal is to develop a targeted therapeutic approach for localized tumors that increases the specificity and efficacy of the therapy and reduces the cytotoxicity in normal tissues. We have developed a thermally responsive polypeptide (CPP-ELP-H1) that inhibits c-Myc transcriptional activity and malignant glioma cell proliferation. The objective of the proposed research is to demonstrate that after systemic administration in vivo, these genetically engineered polypeptides can be targeted to the brain tumor site by applying local hyperthermia and inhibit tumor growth. The amino acid sequence of the thermally responsive polypeptides is based on the elastin-like (ELP) biopolymer, which is soluble in aqueous solution below physiological temperature (37 0C), but aggregates when the temperature is raised above 41 0C. A cell-penetrating peptide (CPP), Bactenecin (Bac) or Tat, is conjugated to the ELP to enhance delivery of the polypeptide across the blood brain barrier and to facilitate cell entry. To the CPP-ELP is added a peptide derived from helix 1 (H1) of the helix-loop-helix domain of c-Myc, which inhibits transcriptional activation by c-Myc and consequently inhibits cancer cell proliferation. Our hypothesis is that intravenously delivered thermally responsive c-Myc inhibitory polypeptides are likely to be cleared under physiological conditions (37 0C). However, they will accumulate in gliomas grown in rat brains, where externally induced local heat (40-42 0C) will be applied. The accumulated polypeptides will block c-Myc activity and consequently inhibit proliferation of the cancer cells. In order to address this hypothesis, the following specific aims will be addressed: (1) measure the plasma kinetics and in vivo distribution of CPP-ELP-H1 in normal and neoplastic tissue and (2) evaluate the therapeutic efficacy of CPP-ELP-H1 in the treatment of neoplastic brain tumors in rats through repeated administration of the agent coupled with and without local hyperthermia. Successful completion of the proposed study will provide the first evidence that ELP can deliver a therapeutic molecule and reduce brain tumor size in a thermally targeted manner, and this work will obtain the necessary toxicity, pharmacokinetic, biodistribution, and efficacy data necessary to advance this technology toward the ultimate goal of human therapeutics. Therefore, proposed research may have a significant impact, leading this technology into clinical trials, and it may provide a powerful technology to treat and manage brain tumors.
Glioblastoma is the most common and most aggressive of the primary brain tumors. Despite advances in combined treatment regimens including surgery, radio- and chemotherapy, the prognosis of a glioblastoma diagnosis is still bleak due to poor blood- brain barrier penetration of therapeutics, resistance to chemotherapeutic agents and nonspecific cytotoxicity in normal tissues. Motivated by the limitations of current therapeutic approaches for treatment of glioblastoma, the objective of the proposed research is to develop a thermally responsive therapeutic polypeptide which can be targeted to the brain tumor site by applying local hyperthermia and inhibit its growth.
