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.
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.
| Sharma, Shweta; Mann, Aman P; Mölder, Tarmo et al. (2017) Vascular changes in tumors resistant to a vascular disrupting nanoparticle treatment. J Control Release 268:49-56 |
| Hunt, Hedi; Simón-Gracia, Lorena; Tobi, Allan et al. (2017) Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles. J Control Release 260:142-153 |
| Sharma, Shweta; Kotamraju, Venkata Ramana; Mölder, Tarmo et al. (2017) Tumor-Penetrating Nanosystem Strongly Suppresses Breast Tumor Growth. Nano Lett 17:1356-1364 |
| Ruoslahti, Erkki (2017) Tumor penetrating peptides for improved drug delivery. Adv Drug Deliv Rev 110-111:3-12 |
