Bench to Bedside
“Science is driven by compassion and empathy often to alleviate the pains of humanity”
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At Ahmed Lab, our core belief is in the vital importance of translational research for brain tumors. We are dedicated to taking the knowledge we gather from basic research and leveraging it to identify and validate new druggable targets in preclinical animal models. By doing so, we aim to pave the way for the initiation of new clinical trials.
We are thrilled to announce the initiation of our inaugural clinical trial, which aims to evaluate the efficacy of an FDA-approved drug repurposed to target plasticity-driven chemoresistance in brain tumors. We extend our heartfelt gratitude to all present and former lab members who have contributed to this project over the years. This groundbreaking endeavor originated nearly a decade ago when Brenda Auffinger, MD, and Alex Tobias, MD, first demonstrated that the anti-cancer chemotherapy temozolomide could induce cellular plasticity-driven cancer stem cell niche, potentially leading to therapeutic resistance.
The dedicated efforts of Gina Lee MD, Tanwir Hasan, Seamus Caragher, and others have delved into unraveling the molecular mechanisms underlying therapeutic stress-induced cellular plasticity. Their research has shed light on the crucial role of chromatin remodeling in driving plasticity-mediated therapeutic adaptation. Over the past five years, Jack Shireman, Fathema Atashi, Ph.D., Ella Perrault, Dr. Park, and our collaborative efforts with NW neurooncologists, Drs. Priya Kumthekar and Roger Stupp have focused on identifying druggable targets to counteract plasticity during therapy. Notably, we have demonstrated the potential of an FDA-approved drug, mycophenolate mofetil, currently utilized in the transplant setting, to mitigate chemoresistance in animal models (Brain 2021).
As a result of our collective contributions, we are thrilled to announce the commencement of our Phase I/Ib clinical trial (NCT052360223), which is actively enrolling patients diagnosed with glioblastoma. This collaborative endeavor holds immense promise in advancing our understanding and treatment of this challenging disease.
Clinical Trial Contact: Priya U. Kumthekar, MD
Phase 1 safety study is completed
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Preparing for Phase 2/3
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Phase 1 safety study is completed • Preparing for Phase 2/3 •
Our recent report identified a protein called RRM2 that plays a key role in GBM's resistance to temozolomide (TMZ) therapy. By promoting metabolic adaptation and tumor recurrence, RRM2 contributes to GBM's ability to survive treatment. We believe targeting RRM2 and its associated pathway, RNR, could be vital in overcoming GBM chemoresistance.
Triapine (3-AP), a second-generation inhibitor with improved effectiveness, holds promise in sensitizing GBM cells to TMZ therapy. Our collaboration with Nanopharmaceutic, a company holding the patent for clinical-grade 3-AP, aims to explore its potential against different GBM subtypes. Our preliminary data show promising results.
Based on this report, we have opened a Phase 1/1b clinical trial to evaluate the combination of 3-AP and standard chemotherapy TMZ for recurrent GBM in the near future. This trial aims to assess the safety and toxicity of this innovative combination and determine the highest tolerable dose. Additionally, we will explore secondary endpoints such as progression-free survival and overall survival, providing valuable insights into the potential of this treatment approach.
By translating our laboratory findings into clinical practice, we hope to overcome chemoresistance in GBM and improve patient outcomes. Our research presents a promising opportunity to target the RRM2-mediated pathway using an FDA-approved drug like 3-AP. This work represents a significant step towards finding more effective treatments for this devastating disease.
Clinical Trial Contact: Karan Dixit, MD
Karan.Dixit@nm.org