SBIR-STTR Award

Glioblastoma multiforme (GBM) or 'glioblastoma,' is the most common and aggressive malignant primary brain tumor in humans. An effective treatment that increases patient survival would represent a significant advance in the field, and provide a desperately needed new therapy for this deadly disease. EnduRx is focused on the development of new, targeted systems for cancer treatment. Our collaborators, at the Sanford-Burnham Medical Research Institute (SBMRI), led by Prof. Ruoslahti, have developed an exciting new tumor targeted nanosystem for cancer therapy. This nanosystem has shown unprecedented anti- cancer activity in highly drug resistant/refractory mouse models of glioblastoma, which closely mimic the human disease. We have identified new homing peptides that can carry nanoparticles deep into the target tissue. Phase I of this application will test whether these new tissue penetrating, homing peptides can improve the efficacy of the nanosystem. Support of this Fast-Track SBIR application will enable selection of a preclinical candidate and accelerate the development of a new therapeutic for GBM and other cancers, via the following aims: Phase I: Optimization of CGKRK-D(KLAKLAK)2-NWs Aim 1. Synthesis of CGKRK-(homing peptide)-D(KLAKLAK)2-NW analogues. Aim 2. Assay new constructs to confirm p32-binding and cell and tissue penetration The most promising p32 homing peptide-D(KLAKLAK)2-NW analogue identified in Phase I will advance into further development in Phase II. Phase II: In vivo efficacy studies, product development and pilot toxicology Aim 1. In vivo pharmacology Aim 2. Synthesis and analysis of candidate p32-homing peptide-D(KLAKLAK)2-NWs Aim 3. Pharmacokinetic studies and second species selection for safety Aim 4. Dose-escalating toxicology in rodents: determine dose range for toxicology studies At the end of Phase II, a clinical development candidate will have been identified that is ready to enter GLP toxicology studies, in support of an IND submission for development of a new, safe and effective treatment for cancer. In addition, the iron oxide component serves as a MRI contrast agent for diagnostic imaging.

Thesaurus Terms:
Analog;Apoptotic;Binding (Molecular Function);Biological;Biological Assay;Brain Tissue;Cancer Diagnosis;Cancer Therapy;Canis Familiaris;Cell Surface;Cells;Chemotherapy;Clinical;Contrast Media;Coupled;Coupling;Cutaneous;Data;Design;Development;Diagnostic Imaging;Disease;Dose;Drug Formulations;Drug Kinetics;Drug Resistance;Effective Therapy;Glioblastoma;Goals;Hand;Head;Homing;Human;Human Disease;Improved;In Vitro;In Vivo;Iron Oxide;Lead;Magnetic Resonance Imaging;Malignant - Descriptor;Malignant Neoplasms;Medical Research;Meetings;Methods;Modeling;Mouse Model;Nanoparticle;Nanosystems;Neuroglia;Novel;Novel Therapeutics;Organ;Patients;Penetration;Peptide Analog;Peptides;Pharmaceutical Preparations;Pharmacology;Phase;Phase 2 Study;Plasma;Pre-Clinical;Primary Brain Neoplasms;Product Development;Protocols Documentation;Public Health Relevance;Radiation;Rattus;Receptor;Refractory;Research Institute;Resistance;Rodent;Rodent Model;Route;Safety;Selective Expression;Small Business Innovation Research Grant;Surface;System;Targeted Delivery;Testing;Tissue Sample;Tissues;Toxic Effect;Toxicology;Tumor;Tumor Tissue;

Glioblastoma multiforme (GBM) or "glioblastoma," is the most common and aggressive malignant primary brain tumor in humans. An effective treatment that increases patient survival would represent a significant advance in the field, and provide a desperately needed new therapy for this deadly disease. EnduRx is focused on the development of new, targeted systems for cancer treatment. Our collaborators, at the Sanford-Burnham Medical Research Institute (SBMRI), led by Prof. Ruoslahti, have developed an exciting new tumor targeted nanosystem for cancer therapy. This nanosystem has shown unprecedented anti- cancer activity in highly drug resistant/refractory mouse models of glioblastoma, which closely mimic the human disease. We have identified new homing peptides that can carry nanoparticles deep into the target tissue. Phase I of this application will test whether these new tissue penetrating, homing peptides can improve the efficacy of the nanosystem. Support of this Fast-Track SBIR application will enable selection of a preclinical candidate and accelerate the development of a new therapeutic for GBM and other cancers, via the following aims: Phase I: Optimization of CGKRK-D(KLAKLAK)2-NWs Aim 1. Synthesis of CGKRK-(homing peptide)-D(KLAKLAK)2-NW analogues. Aim 2. Assay new constructs to confirm p32-binding and cell and tissue penetration The most promising p32 homing peptide-D(KLAKLAK)2-NW analogue identified in Phase I will advance into further development in Phase II. Phase II: In vivo efficacy studies, product development and pilot toxicology Aim 1. In vivo pharmacology Aim 2. Synthesis and analysis of candidate p32-homing peptide-D(KLAKLAK)2-NWs Aim 3. Pharmacokinetic studies and second species selection for safety Aim 4. Dose-escalating toxicology in rodents: determine dose range for toxicology studies At the end of Phase II, a clinical development candidate will have been identified that is ready to enter GLP toxicology studies, in support of an IND submission for development of a new, safe and effective treatment for cancer. In addition, the iron oxide component serves as a MRI contrast agent for diagnostic imaging.

Public Health Relevance Statement:


Public Health Relevance:
Glioblastoma (GBM) is one of the most aggressive and fastest growing of human cancers. Even with the best available treatment, the median survival is less than 15 months. This daunting scene highlights the desperate need to develop novel effective therapies for glioblastoma. A new effective approach to increase patient survival would represent a significant advance in the field, and provide an urgently needed new therapy for this deadly disease. With preliminary proof of concept and efficacy data in hand, we propose to develop an novel- targeted nanosystem for the effective treatment of glioblastoma.

NIH Spending Category:
Bioengineering; Brain Cancer; Brain Disorders; Cancer; Diagnostic Radiology; Nanotechnology; Neurosciences; Orphan Drug; Rare Diseases

Project Terms:
analog; Apoptotic; Binding (Molecular Function); Biological; Biological Assay; brain tissue; cancer diagnosis; cancer therapy; Canis familiaris; Cell surface; Cells; chemotherapy; Clinical; Contrast Media; Coupled; Coupling; Cutaneous; Data; design; Development; Diagnostic Imaging; Disease; Dose; Drug Formulations; Drug Kinetics; Drug resistance; effective therapy; Glioblastoma; Goals; Hand; Head; Health; Homing; Human; human disease; improved; In Vitro; in vivo; iron oxide; Lead; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Medical Research; meetings; Methods; Modeling; mouse model; nanoparticle; nanosystems; Neuroglia; novel; novel therapeutics; Organ; Patients; Penetration; peptide analog; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; phase 2 study; Plasma; pre-clinical; Primary Brain Neoplasms; product development; Protocols documentation; radioresistant; Rattus; receptor; Refractory; Research Institute; Rodent; Rodent Model; Route; Safety; selective expression; Small Business Innovation Research Grant; Surface; System; targeted delivery; Testing; Tissue Sample; Tissues; Toxic effect; Toxicology; tumor; Tumor Tissue