The CHEMOWARRIOR Foundation is helping to fund exciting Ewing sarcoma research being conducted at the Mary Crowley Cancer Research Center. The money we raised in 2014 – 2016 went towards the development of the targeted therapy drug described below and the opening of a Phase 1 clinical trial in 2017 that is currently recruiting patients.
Mary Crowley Cancer Research Centers
Cancer drugs and treatment for children and adolescent cancers is an afterthought to those for adults. It can take decades for scientific breakthroughs to reach this population. Mary Crowley has a unique opportunity to leverage our success with adult cancers and accelerate these new therapies to children and adolescents.
Ewing’s Targeted Therapy Preclinical Development to Phase 1 Clinical Trial
At Mary Crowley Cancer Research Centers, our collaborative team has designed a promising targeted therapy for Ewing sarcoma. Ewing sarcoma tumors are associated with chromosomal translocation between the EWS gene and the ETS transcription factor gene. Because the gene abnormality is well defined for EWS, these unique target sequences provide opportunity for RNA interference(i) based therapy. RNA interference is a natural process through which expression of a targeted gene is knocked down with high specificity and selectivity. The specific RNAi targeted therapy available at Mary Crowley is called bi-functional shRNA interference ( bi-shRNA). Utilizing this bi-functional technology, the RNAi structure is modified to take advantage of the natural silencing machinery within the cell. The identification of the EWS/FLI-1 oncogenic fusion gene and demonstration of its broad-based expression in Ewing sarcoma makes RNAi application to Ewing sarcoma timely to advance as a promising potential therapy. Mary Crowley has the opportunity to take this innovative new technology from the laboratory to patients in a clinical trial. The initial in vitro (cell lines) testing of this technology revealed >92% knockdown of the fusion gene. We then moved into in vitro testing with mice models to access tumor growth reduction. Initials results showed 75% less tumor growth in mice that received the treatment versus those mice that did not receive the treatment. We are encouraged by these positive results and will continue moving forward with preclinical development through Phase 1 clinical trial.
Ewing Sarcoma Project bi-shRNAEWSFLI1– Project Update from Mary Crowley on 2/13/15
Manufacture DNA for toxicology / bio-distribution studies and clinical trial
We are expecting delivery of approximately 3.5 grams of cGMP plasmid DNA from Waisman manufacturing on February 24, 2015. Upon receipt, Strike Bio will begin manufacturing the pGBI-140 lipoplex for the remaining pre-clinical studies and the Phase 1 clinical trial.
The manufacturing of the lipoplex should be complete in mid-March, and then Altogen Labs, a Good Laboratory Practice (GLP) compliant laboratory that provides biotechnology research services for pharmaceutical, biotechnology, and academic institutions worldwide, will conduct a maximum tolerated dose study (MTD) in mice. This will provide guidance for the therapeutic dose for the Phase 1 clinical trial. The toxicology and bio-distribution studies will follow.
Study design bids were submitted to various laboratories for the studies and Charles River will be conducting the toxicology study and MPI Research, a reputable research firm in Michigan, will be conducting the bio-distribution study. Both studies are estimated to run 6 months or less with pathology and plasmid analysis done concurrently.
Discussions with the FDA and IND preparation will also be conducted during these study periods with the goal of submission in November 2015, to initiate a Phase 1 clinical trial in late December 2015 or early January 2016.
Testing of this Targeted Therapy in Adult Cancers
The bi-functional shRNA technology in development for Ewing’s has been shown to safely target genetic abnormalities in multiple adult cancers. Adult cancer testing to date of the shRNA technology includes:
- A Phase 1 Clinical Trial is being conducted to target Stathmin1, a genetic mutation found in many adult cancers, via an intratumoral injection and dose escalating treatment. Initial results supported expanding this phase 1 trial and moving into an intravenous infusion.
- Other preclinical work of this bi-functional technology revealed mechanism to silence target genes, effectively knocking down the target, with constructs made for 17 gene mutations.
Other exciting Ewing’s Sarcoma research is also being conducted at Mary Crowley, including:
Ewing’s Phase 1 Personalized Vaccine Clinical Trial
Mary Crowley has a Phase 1 personalized vaccine trial underway for patients with advanced Ewing’s Sarcoma that have relapsed and have failed standard treatment. This vaccine is made from each patient’s own tissue, which targets Ewing’s sarcoma cancer receptors unique to each patient. The body’s immune system is capable of rejecting the growth of tumors, but it is handicapped because of the cancer’s evolving defense mechanisms. Cancer vaccines can be used for treatment, rather than prevention, by educating the immune system to recognize and fight the cancer. We have shown that the vaccine called FANG™ can overcome the cancer’s block on the immune system through utilization of a novel RNA interference technology. We have treated late-stage adult cancer patients with FANG™, with no side effects and extended survival compared to historical experience. Due to these non-toxic and dramatic results, FDA approval was secured to treat children with Ewing’s sarcoma with the FANG™ vaccine and we have successfully made vaccines for 12 children. We have treated 8 children without side effects. Limited initial data shows immune system activation. We will continue to examine the hypothesis that FANG™ is safe and effective for inducing an anti-tumor response in children with Ewing’s sarcoma. Once clinical benefit is proven we will begin plans to move forward to Phase 2. We will use the genetic data obtained in Ewing’s Sarcoma to further accelerate other vaccine trials to advance new treatments for all childhood cancers.
Our goal is to complete patient accrual by July of 2014. After assessment of phase 1 data, we will begin interaction with the FDA for Phase 2 trial design and approval. We would expedite opening the Phase 2 trial upon FDA approval in 2015.
FANG™ Vaccine Adult Cancer Trials
- A Phase 1 trial was conducted with many different types of advanced cancers. Safety and correlated immune response with survival was demonstrated. Seventy four (74) patients were treated with a median extended survival of 562 days.
- Phase 1 trials are ongoing for adult cancers.
- A Phase 2 randomized ovarian cancer trial is currently underway at Mary Crowley and other locations in Dallas, Fort Worth, and Palm Beach, FL.