R01CA260340

Addressing Chemoresistance in Pancreatic and Ovarian Cancers: Photodynamic Priming and Repurposing of Tetracyclines Using Targeted Photo-Activable Multi-Inhibitor Liposome - Abstract

The prognosis for patients with advanced stage ovarian or pancreatic cancer has remained dismal for decades. The poor response rates result, in part, from resistance to salvage chemotherapies, including topoisomerase I (TOP1) inhibitors such as irinotecan and topotecan.

The full potential of TOP1 inhibitors is hindered mainly by two mechanisms: (1) ATP-binding cassettes (ABC) transporters (i.e., P-glycoprotein and ABCG2) that actively pump drugs out of cancer cells, and (2) upregulation of the DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1, which resolves the TOP1-DNA cleavable complexes to allow DNA re-ligation and cell proliferation.

It is becoming increasingly clear that no single treatment is likely to overcome this complex problem, and combination treatments of newly emerging modalities may offer the most promise. Here, we introduce a complementary, two-pronged approach to address chemoresistance: (I) employing photodynamic priming (PDP) to damage ABC transporters, improve the delivery of TOP1 inhibitors, and reduce the normal tissue toxicity, and (II) repurposing tetracycline antibiotics to inhibit the DNA damage repair enzyme tyrosyl-DNA phosphodiesterase 1.

PDP is a clinically relevant, photochemistry-based modality that involves light activation of photosensitizers to modulate nearby tissues or biomolecules without killing the cells. This proposal leverages image-guided strategies and nanoscale engineering to develop targeted photo-activable multi-inhibitor liposome (TPMIL) that co-delivers PDP, TOP1 inhibitors, and tetracycline antibiotics in the appropriate sequence with consideration of their mechanistic interactions.

In addition to co-packaging TOP1 inhibitors and antibiotics, TPMIL is surface modified with antibody-photosensitizer conjugates to target epidermal growth factor receptor, which is frequently amplified in pancreatic and ovarian cancer.

Using a novel hyperspectral fluorescence microendoscope imaging system, we will longitudinally monitor photosensitizer delivery and changes in ABC transporter expression to improve PDP and chemosensitization in vivo (Aim 1). The mechanistic interactions between TOP1 inhibitors and tetracycline antibiotics will be investigated in vivo, with and without PDP (Aim 2). Biomarkers predictive of chemosensitization will also be identified.

TPMILs will be customized to target ovarian and pancreatic cancer cells while co-delivering photosensitizers, TOP1 inhibitors, and tetracycline antibiotics (Aim 3). The safety and therapeutic efficacy of TPMIL will be determined in PDX mouse models (Aim 4).

We have demonstrated the clinical feasibility of PDP in patients with locally advanced pancreatic cancer. For metastatic ovarian cancer, we envision a simple and feasible modification to the standard clinical framework. TPMILs will be delivered intraperitoneally after surgical debulking of ovarian tumors, and then light activated to trigger PDP and the release of chemotherapy and antibiotics.

The knowledge gained may play a transformative role in the development of improved therapeutic regimens that are tailored to the molecular profile of advanced pancreatic and ovarian cancer in individual patients.

College Park University Of Maryland

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

College Park, Maryland 207420001 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 378% from $673,220 to $3,218,280.