The Glioblastoma Drug Discovery Group announces that osimertinib significantly prolongs the survival of immunocompromised mice bearing intracranial EGFRvIII-positive glioblastoma! These data warrant the commencement of studies designed to test osimertinib’s safety and efficacy in GBM patients.
The Glioblastoma Drug Discovery Group is proud to have brain tumor survivor, Dr. Steven Keating, Ph.D., as a volunteer advisor. Dr. Keating is a strong proponent of curiosity and open patient data, having discovered his own brain tumor during a voluntary academic scan. Since Dr. Keating had a successful brain tumor removal surgery via awake craniotomy in 2014, he has a unique and powerful perspective on the future of brain tumor therapies. He will help us accelerate the development and characterization of our preclinical models for the adolescent and young adult age category. We are very excited to have Dr. Keating join our team!
The Musella Foundation has graciously funded fellowships for two Duke University students, Bradley Cahn and Blair Wilette, to contribute to a project in the lab of Dr. Madan Kwatra. The NIH/NCATS research project they will be working on is titled “Targeting GBMs with Activated EGFR with third-generation, brain penetrating AZD9291.” You can read more about this project in this press release from Duke Translational Medicine: https://www.dtmi.duke.edu/news/can-lung-cancer-drug-fight-brain-tumors
Follow here for updates on their work and what they are learning.
With the help of the Nicki Leach Foundation, our lab is working to develop preclinical models for glioblastoma brain tumors found in adolescents and young adults (AYA). This group of tumors is biologically distinct and unique from glioblastoma tumors seen in older patients. Thus, this group warrants its own preclinical models to develop effective therapies. A newly uncovered misconception with this age group is that although AYA traditionally have significantly longer survival than older patients, while the the older age group’s cancer survival has been improving overall, AYA has not experienced any increase in survival and now may have worse survival than the older patients. This is likely due to improper models to develop effective therapies for this age category.
We have decided to group the patients as follows:
- Adolescents: Ages 14-29
- Young adults and adults: Ages 30-45
- Mature adults and elderly: Ages 46+
The examination of 595 GBM samples analyzed by TCGA, twenty-four samples existed that were in age range of 14 to 29. Therefore, this age category composes just 4% of the total GBM patients categorized.
Quinn T. Ostrom, Haley Gittleman, Peter M. de Blank, Jonathan L. Finlay, James G. Gurney, Roberta McKean-Cowdin, Duncan S. Stearns, Johannes E. Wolff, Max Liu, Yingli Wolinsky, Carol Kruchko, and Jill S. Barnholtz-Sloan. American Brain Tumor Association Adolescent and Young Adult Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro Oncol (2016) 18 (suppl 1): i1-i50 doi:10.1093/neuonc/nov297
On June 2, 2020, Dr. Kwatra and his collaborators published their findings on osimertinib’s efficacy against EGFRvIII+ glioblastoma in the journal Oncotarget.
The study began in 2015 when Dr. Kwatra and his co-PI, Dr. Glenn Lesser at Wake Forest University, received a grant from NIH/NCATS and AstraZeneca. At the time, AstraZeneca was developing osimertinib, then called AZD9291, for lung cancer patients. Osimertinib was approved by the FDA for lung cancer patients in 2015. Preliminary findings of our follow-up study were published at the 2017 Society of Neuro-Oncology meeting.
This new study shows that EGFRvIII+ GBMs are heterogeneous, and osimertinib may be effective in some patients with EGFRvIII+ GBM tumors. Future studies are planned to identify the molecular characteristics of EGFRvIII+ tumors that make the tumor most sensitive to osimertinib. Once this information is obtained, osimertinib will be tested in a refined, specific group of EGFRvIII+ GBM patients.
Osimertinib, as Dr. Kwatra detailed in his 2017 review, is the most promising EGFR blocker tested so far in GBM patients because it penetrates the brain well and potently inhibits the growth of EGFRvIII+ GBMs with higher EGFRvIII tyrosine kinase activity. Failure of previous drugs targeting EGFR (such as afatinib, erlotinib, gefitinib, and lapatinib) can be explained by 1) the fact that they do not penetrate the brain well and 2) the studies of past EGFR inhibitors were done on a broad spectrum of patients without molecularly profiling their tumors. However, our understanding of GBM tumor heterogeneity has increased considerably, and now we can study these drugs correctly.
Thus, we are confident that osimertinib will show an effect in a subset of molecularly-defined patients. Dr. Kwatra and his collaborators at Cornell-Weil, Johns Hopkins, National Cancer Institute, and University of Alabama at Birmingham continue to work on the personalized development of osimertinib to ensure the promising drug receives FDA approval for a subset of GBM patients with specific molecular characteristics. Furthermore, preliminary studies on GBM patients conducted by Dr. Lesser show benefits of osimertinib therapy. Please read our new publication here.
Dr. Madan Kwatra, Director of Glioblastoma Drug Discovery Group, is pleased to announce his recent R01 grant submission to the National Cancer Institute for 4 million dollars over 5 years. This grant will be used to fund a phase II clinical trial of osimertinib (AZD9291) in newly diagnosed EGFRvIII+ glioblastoma patients. This trial is in collaboration with Wake Forest School of Medicine, Johns Hopkins School of Medicine, and University of Alabama at Birmingham.
The Musella Foundation has again graciously funded fellowships for two Duke University students, Josh Engel and Caroline Maretz, to contribute to a project in the lab of Dr. Madan Kwatra during the summer of 2018. The two students will be contributing to a project studying the heterogeneity of EGFRvIII-positive glioblastoma and their sensitivity to AZD9291 (Osimertinib).
Follow here for updates on their work and what they are learning during the summer.
Dr. Madan Kwatra, Director of the Glioblastoma Drug Discovery Group at Duke, is pleased to announce that the FDA has approved the group’s IND entitled: “Phase II evaluation of osimertinib in newly diagnosed glioblastoma patients expressing EGFRvIII.” Dr. Kwatra is planning to conduct a randomized, multi-center trial to test the efficacy of osimertinib in EGFRvIII-positive GBM patients. A key feature of the trial will be a comprehensive characterization of each patient’s tumor as well as the establishment of PDX and stem cell models from each patient’s tumor.
The Amelia Garcia Fund at The Miami Foundation has presented The Glioblastoma Drug Discovery Lab at Duke University with a $2000 grant. The grant is designated specifically toward our adolescent and young adult (AYA) project, which aims to develop preclinical models to test therapies against glioblastoma in patients of ages 15 to 39 years. The Amelia Garcia fund was started in the memory of Mrs. Amelia Garcia, who died of glioblastoma at the age of 30.
The AYA project was of special interest to the Amelia Garcia Fund because its mission is to develop therapies to treat younger GBM patients. Please read more about our AYA project here:
Dr. Madan Kwatra, Director of the Glioblastoma Drug Discovery Group at Duke, gave an oral presentation at the 2017 annual meeting for the Society of Neuro-Oncology (SNO) held in San Francisco from November 16 to 19. The presentation was entitled: A Precision Medicine Approach to Target EGFRvIII in GBM: Osimertinib (AZD9291) Inhibits the Growth of EGFRvIII-Positive Glioblastoma Stem Cells and Increases Survival of Mice Bearing Intracranial EGFRvIII-Positive GBM. Collaborators included: Cory Nanni, Callie Roberts, Shawn Kwatra, Mark R Gilbert, Glenn J Lesser.
Genzada Pharmaceuticals has awarded Dr. Kwatra, Director of Glioblastoma Drug Discovery Group at Duke, a two-year, $763,200 grant, titled “Evaluation of novel anti-cancer agents, either alone or in combination, for activity against glioblastoma subtypes: a personalized medicine approach.”
Genzada specializes in pharmaceuticals derived from plants. Their lead compounds have shown activity in preclinical models of several cancers and can penetrate the blood brain barrier. Thus, this could potentially give rise to a natural, alternative therapy against GBM. The compounds will be tested against a diverse molecular profile of GBMs, allowing for a personalized and targeted approach.
Read more here: https://anesthesiology.duke.edu/?p=840707
DelMar Pharmaceuticals has entered into a multi-year collaboration with Dr. Madan Kwatra, Director of the Glioblastoma Drug Discovery Group at Duke University for a project entitled, “Development of VAL-083, alone or in combination with other agents, to inhibit the growth of specific subsets of glioblastoma (personalized drug development).” The three-year preclinical study project has a budget of $715,500 and has the goal of improving the standard of care for the management of newly diagnosed glioblastoma (GBM) patients.
GBM is a deadly brain cancer, and attempts to control its progression have failed. The current standard of care consists of surgery followed by radiation and chemotherapy using temozolomide. However, temozolomide only works for about 40% of GBM patients that have a methylated MGMT promoter. In contrast, VAL-083 is a novel chemotherapeutic agent that has activity against GBM with both methylated and unmethylated MGMT promoters. Thus, VAL-083 is a more versatile chemotherapeutic agent that may help a wider subset of GBM patients. The completion of the proposed preclinical studies will identify molecular characteristics of GBM tumors that are more likely to respond to VAL-083 therapy either alone, or through combination therapies. This personalized medicine approach will be used to initiate clinical trials in newly diagnosed GBM patients
Dr. Madan Kwatra, Director of the Glioblastoma Drug Discovery Group at Duke, has been awarded a $97,109 grant for his project titled, “Efficacy of AZD9291 against EGFRvIII-positive glioblastoma.” These studies are a continuation of the NIH/NCATS grant that Dr. Kwatra received in 2015.
Glioblastoma (GBM) is a deadly brain cancer. Thus, Dr. Kwatra and the group believe a personalized medicine approach is required to control the significant inter- and intratumoral heterogeneity of GBM.
The third generation EGFR-TKI, known as AZD9291, has good brain penetration and also blocks EGFRvIII, a mutant EGFR present in 20 percent of GBM tumors, with high affinity. Dr. Kwatra’s preliminary studies indicate AZD9291 is active against EGFRvIII-positive GBMs intracranially transplanted in nude mice. Studies conducted so far indicate that EGFRvIII-positive GBMs differ in their response to AZD9291. The compound will be effective only in GBM patients expressing the sensitive form of EGFRvIII (precision medicine approach).
Read more here:
Glioblastoma in adolescent and young adults (AYA), an age group spanning 15 to 39 years, is molecularly different than glioblastoma in older adults over 50 years of age. Therefore, to develop an effective therapy against GBM in AYA patients, we need to develop preclinical models (glioblastoma stem cells [GSCs] and patient-derived glioblastoma xenografts [PDGX]) from AYA patients for personalized drug development.
The AYA group will be subdivided into five groups (A to E) based on age.
A: 15-19 years; B: 20-24 years; C: 25-29 years; D: 30-34 years; E: 35-39 years
Recent AYA victims of GBM: Beau Biden, age 39, son of former Vice-President Joe Biden; Brittany Maynard, age 29, an advocate of right to die; and David Pearson, age 16, son of cancer research advocate Amanda Haddock.
For each age group, we will develop preclinical models from at least ten patients to capture inter tumor heterogeneity.
Tumor samples will be collected from multiple medical centers, within a 200 mile radius of Duke University, to allow fresh tumor samples to be brought to the laboratory for preclinical model (GSC and PDGX) development and molecular analyses. Fresh tumor samples will be divided into three parts:
- The first part will be used for molecular analyses.
- The second part will be implanted sub-cutaneously in immunocompromised for PDGX development.
- The third part will be used to isolate GSCs.
Primary tumor, PDGX, and GSC from each patient will be subjected to the following analyses:
- Exome sequencing
- DNA methylation
Development of preclinical models and molecular analyses would cost about $40,000/patient (National Brain Tumor Society estimate)
Total project cost: $2 million ($40,000 x 50).
Project duration: 3 years (or less depending on the availability of samples)
Funds needed to start the project: $100,000 for hiring a research assistant/program coordinator to recruit investigators at various centers, to start the IRB process, and for buying of research supplies
Ostrom QT et al. American Brain Tumor Association Adolescent and Young Adult Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro Oncol. 2016 Jan;18 Suppl 1:i1-i50. doi: 10.1093/neuonc/nov297.