R01CA260958

In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy

Cancer nano-formulations for delivery of small molecule drugs are limited by the ability to target only ~10% of the genome. RNAi molecules can, in theory, be designed against any gene of interest, but siRNA use in clinical oncology faces delivery barriers such as nuclease degradation, rapid renal clearance, poor distribution into tumor tissues, and poor cell membrane penetration.

To overcome these challenges, most RNAi therapies focus on synthetic lipo- and poly-plex nano-formulations. Unfortunately, while these technologies typically achieve very high delivery into the liver, high-penetrance siRNA tumor delivery remains elusive.

The overarching goal of this project is to develop siRNA chemical modifications that provide potent, safe, tumor-penetrating, and molecularly targeted nano-therapeutics against currently undruggable tumor drivers. The approach builds upon our recently published proof of principle siRNA molecules end-modified through a PEG45 linker with a diacyl lipid (siRNA-EG45
This albumin "hitchhiking" siRNA-EG45
The specific goal of this proposal is to further explore and optimize siRNA chemical modifications for in situ formation of effective ALB-NCS. We will benchmark new candidates against conventional nano-formulations in simple (xenograft), immune-competent (allograft), and rigorous (PDX and spontaneous) tumor models.

This platform will be validated for silencing of the oncogene myeloid cell leukemia 1 (MCL-1) to treat triple negative breast cancer (TNBC). MCL-1 is a vetted target with relevance in a broad range of cancers, supporting its use for proof-of-concept. Furthermore, TNBC is a highly aggressive clinical breast cancer subtype with few treatment options. TNBC patients are currently relegated to chemotherapies and do not typically benefit from molecularly-targeted therapies.

This project is uniquely accessible by our multi-PI interdisciplinary team with bioengineering expertise in intracellular biologic drug delivery nanotechnologies (Duvall), chemical synthesis (Uddin), analysis of noncoding RNA transport on serum components (Vickers), MCL-1 pathway modulation and analysis (Cook), and cutting-edge preclinical models, including PDX, for testing experimental therapies (Brantley-Sieders).

Our basic science expertise will be supplemented by consultation with Dr. Ingrid Mayer, a medical oncologist involved in breast cancer clinical trials at Vanderbilt. This group will enable previously inaccessible investigations toward development of more effective, tumor-penetrating, and molecularly-targeted TNBC therapeutics.

Vanderbilt University

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]

Nashville, Tennessee 372320001 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 392% from $617,228 to $3,035,458.