Current treatment of solid tumors is limited by normal tissue tolerance, inherent tumor resistance to radiation or chemotherapy, and toxicity from systemic administration of antineoplastic agents. The result is a narrow therapeutic index for most current chemotherapeutic agents. Our long term goal is to overcome these limitations by developing 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 which inhibits cell cycle progression and proliferation of cancer cells in cell culture. The objective of the proposed research is to demonstrate that after systemic administration, these genetically engineered polypeptides can be targeted to the tumor site by applying local hyperthermia. This will results in accumulation of the agent in the tumor with subsequent inhibition of tumor growth. The amino acid sequence of the thermally responsive polypeptides is based on elastin-like (ELP) biopolymers, which are soluble in aqueous solution below physiological temperature (37 oC), but aggregate when the temperature is raised above 41 oC. A cell-penetrating peptide, Bactenecin (Bac) is conjugated to the ELP to facilitate cell entry. To the Bac-ELP is added a peptide derived from the cyclin- dependent kinase inhibitor p21, which inhibits the cell cycle. Our preliminary in vitro results demonstrate a very significant effect of the Bac-ELP-p21 construct in Mat BIII rat mammary adenocarcinoma cells when compared to a non-thermally responsive control peptide. Our hypothesis is that intravenously delivered thermally responsive cell cycle inhibitory polypeptides are likely to be cleared under physiological conditions (37 oC). However, they will accumulate in breast tumors, where externally induced local heat (40-42 oC) will be applied. The accumulated polypeptides will inhibit the cell cycle 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 Bac-ELP-p21 in normal and neoplastic tissue and (2) evaluate the therapeutic efficacy of Bac-ELP-p21 in the treatment of breast tumor in rats through repeated administration of the agent coupled with and without local hyperthermia. The successful completion of the proposed research will provide the basis for a new technology that has a competitive advantage over existing/alternate technologies. These studies will provide the in vivo data necessary to move this therapy towards the translational stage of human therapeutics. Specific targeting of the proposed therapeutic polypeptides to solid tumors by local hyperthermia would increase efficacy of the cancer treatment and reduce the cytotoxicity in normal tissues, and it would provide an alternative means to substitute or augment present therapy for treatment of localized tumors.
Public Health Relevance: Current treatment of solid tumors is limited because only a small fraction of the administered dose of drug reaches the tumor site while the rest of the drug is distributed throughout the body. This causes undesirable side effects to normal tissues when drugs are used in the doses required to eradicate cancer cells. Our long term goal is to overcome this limitation by developing an approach that allows the therapeutics to be delivered specifically to the tumor site. This will increase the specificity of the therapy and reduce the toxicity in normal tissues.
Public Health Relevance Statement: Current treatment of solid tumors is limited because only a small fraction of the administered dose of drug reaches the tumor site while the rest of the drug is distributed throughout the body. This causes undesirable side effects to normal tissues when drugs are used in the doses required to eradicate cancer cells. Our long term goal is to overcome this limitation by developing an approach that allows the therapeutics to be delivered specifically to the tumor site. This will increase the specificity of the therapy and reduce the toxicity in normal tissues.
NIH Spending Category: Breast Cancer; Cancer
Project Terms: Abscission; Address; Adenocarcinoma Cell; Adverse effects; Amino Acid Sequence; Animal Model; Animal Models and Related Studies; Anti-Cancer Agents; Anti-Tumor Agents; Anti-Tumor Drugs; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Arg-Leu-cyclo(Cys-Arg-Ile-Val-Val-Ile-Arg-Val-Cys)-Arg; Biopolymers; Blood Circulation; Blood Plasma; Bloodstream; Body Tissues; Breast Adenocarcinoma; Breast Cancer Model; Breast Neoplasms; Breast Tumors; CAP20 protein; CDK-Interacting Protein 1; CDK2-associated protein 20 kDa; CDKN1 protein; CDKN1A; CDKN1A Protein; CIP-1 Protein; Cancer Drug; Cancer Radiotherapy; Cancer Treatment; Cdk2 inhibitor protein; Cell Culture Techniques; Cell Cycle; Cell Cycle Inhibition; Cell Cycle Progression; Cell Division Cycle; Cell Growth in Number; Cell Multiplication; Cell Proliferation; Cells; Cellular Proliferation; Chemotherapeutic Agents, Neoplastic Disease; Cip1 protein; Circulation; Clinical Trials; Clinical Trials, Unspecified; Code; Coding System; Common Rat Strains; Coupled; Cyclin-Dependent Kinase Inhibitor 1A; Data; Dose; Drug usage; Drugs; Elastin; Engineering; Engineerings; Excision; Extirpation; Fever; Goals; Heating; Human; Human, General; Hyperthermia; IV drip; In Vitro; Injection of therapeutic agent; Injections; Intravenous Drip; Intravenous Infusion; Kinetic; Kinetics; Local Hyperthermia; Lytotoxicity; MDA 6; Malignant Cell; Malignant Glandular Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Mammals, Rats; Mammary Cancer; Mammary Neoplasms; Mammary adenocarcinoma; Man (Taxonomy); Man, Modern; Measures; Mediating; Medication; Modeling; Normal Tissue; Normal tissue morphology; Operation; Operative Procedures; Operative Surgical Procedures; Outcome; P21; Peptides; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiologic; Physiological; Pic-1 protein (cyclin); Plasma; Protein Structure, Primary; Pyrexia; Quantitative Autoradiography; Radiation; Radiation therapy; Radiolabeled; Radiotherapeutics; Radiotherapy; Rat; Rattus; Removal; Research; Resistance; Rest; Reticuloendothelial System, Serum, Plasma; Serum, Plasma; Site; Solid Neoplasm; Solid Tumor; Solutions; Specificity; Staging; Surgical; Surgical Interventions; Surgical Procedure; Surgical Removal; Technology; Temperature; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Toxicities; Toxicity due to chemotherapy; Transition Temperature; Treatment Efficacy; Treatment Side Effects; Tumor Cell; Tumor Volume; Tumor-Specific Treatment Agents; WAF-1 Protein; WAF1 CIP1; WAF1 protein; anticancer agent; anticancer drug; anticancer therapy; aqueous; bactenecin; base; cancer cell; cancer therapy; cdn1 protein; chemotherapeutic agent; chemotherapy; chemotherapy toxicity; clinical investigation; cyclin-dependent kinase Inhibitor p21; cytotoxicity; design; designing; drip infusion; drug use; drug/agent; febrile; febris; in vivo; inhibitor; inhibitor/antagonist; intravenous administration; irradiation; mammary cancer model; mammary tumor; mammary tumor model; mda-6 protein; model organism; neoplastic; neoplastic cell; new technology; oncoprotein p21; p21 cell cycle regulator; p21 cyclin kinase inhibitor; p21(cip1); p21(waf1-cip1); p21-WAF1; polypeptide; protein p21; protein sequence; public health relevance; radiolabel; radiotracer; ray (radiation); resection; resistant; senescent cell-derived inhibitor protein 1; side effect; site targeted delivery; surgery; targeted delivery; therapeutic efficacy; therapeutic target; therapeutically effective; therapy adverse effect; treatment adverse effect; tumor; tumor growth; uptake; vein infusion
