GRANT: $75,000 to CC-TDI for The SISU Project
One year after learning the term “Ewing’s Sarcoma” the hard way, the Spada Pediatric Sarcoma Foundation is proud to announce our first research grant. After digging deep on the science, we’re granting $75,000 to the Children’s Cancer Therapy Development Institute (cc-TDI) to co-fund promising research in maintenance therapy.
While this grant is worthy of a jumbo check, like so many things this year, it has to be a virtual jumbo check.
Dr. Charles Keller (front, center) and some of the brilliant and dedicated team at cc-TDI.
The Birth of a Maintenance Protocol: Preventing Relapse
The standard frontline therapy for children diagnosed with Ewing’s Sarcoma (EWS) consists of 6 - 8 rounds of chemotherapy (neoadjuvant), followed by local control consisting of surgery and/or radiation, then another 6-9 rounds of chemotherapy (adjuvant). This intensive regimen will work in taking most patients to remission by the completion of treatment.[1] However, EWS has many nasty tricks up its sleeve, and at least one-quarter of all patents with localized disease will relapse after this intensive therapy. These odds are worse for children that initially present with metastatic disease.[1] However, these statistics only consider follow-up at the “standard” 5-year mark (a topic for another day). Longer-term relapses, although not as common, can occur at 10, 20, even 30 years out.[2]
Why the need?
How and why relapse occurs is still a mystery, with some researchers alluding to quiescent, hibernating cancer stem-like cells (CSC) as the likely cause,[3] while other researchers point to other differentiated cells gone rogue.[4] Regardless, in both scenarios the exact trigger(s) for relapse is not well understood and remains largely unknown.
The concept of a maintenance therapy is not exclusive to Ewing’s Sarcoma. The central idea to all maintenance therapy, given closely after frontline therapy, is a treatment option (drug, vaccine, or antibody) to help keep patients in remission - permanently if possible.
Examples of successful maintenance therapies exist for other forms of cancer, such as acute lymphoblastic leukemia (ALL) and Multiple Myeloma (MM). [5, 6] In the 1960s, ALL was a universally fatal diagnosis. Now, in part due to continued therapies that prevent relapse from occurring, there is an overall cure rate of greater than 90%.[7] Preventing relapse is key to improving survivorship. Similar types of maintenance (or continued) therapies are needed for Ewing’s Sarcoma, where the current standard of care (chemotherapy, surgery, and/or radiation) has reached a therapeutic plateau over the past 2 decades.[8]
Sisu(n.) Extrodinary determination, courage, and resoluteness in teh face of extreme adversity. An action mindset which enables individuals to reach beyond their present limitations, take action against all odds and .png
What is it?
The SISU Project (named after the Finnish concept that loosely translates to “true grit” or “determination”) was started by a patient family who saw the need to do more. After having been in a wait-and-see holding-pattern themselves, all while observing other EWS patients ahead of them facing relapse, it was obvious that frontline therapy alone was not enough. From there, the goal was easy to define: to find a viable maintenance option for our kids and prevent a relapse. How and who to carry out this research with direct input from patient families, was the bigger question.
The laboratory most inclined to take on this challenge is the small but mighty lab, the Children’s Cancer Therapy Development Institute (cc-TDI) in Beaverton, OR. Led by scientific director Dr. Charles Keller MD, cc-TDI is on a mission to make childhood cancer universally survivable - a bold but welcomed stance as childhood cancer is severely underfunded and consequently under-researched.
As a non-profit, part of the magic of cc-TDI is that it relies heavily on its parent / patient community both to help fund and drive research topics, but also to hold its scientists accountable. Ultimately, this same community is the one most impacted by the outcomes of this research.
cc-TDI’s track record in a scant 5 ½ years of existence, has brought 2 drugs to 3 clinical trials - a massive feat for any lab, let alone one that has no vested financial interest in a drug succeeding. They are truly powered by their mission to save lives: they’re passionate, they’re determined, they’re scrappy, and just the type of scientists you want in your corner. Their science is world-class and they accomplish more than much bigger, traditionally funded labs.
We are excited to announce the SPS Foundation has committed to co-funding Year 2 of this research. In short, the scope of Year 2 research takes the leading 12 drug candidates screened in 4 different cell lines in Year 1 (in vitro studies), and hones in on the leading 3 candidates to be tested in immunocompromised mice (in vivo studies) (Figure 1).
Figure 1. Overview of SISU Project Year 1 and 2 (Courtesy of cc-TDI).
Figure 1. Overview of SISU Project Year 1 and 2 (Courtesy of cc-TDI).
Although specific results cannot be shared at this time (Year 1 and Year 2 will be published in a peer reviewed journal), a class of drugs referred to as HDAC (Histone Deacetylase) inhibitors have been universally promising in all cell lines tested in vitro. Briefly, HDAC inhibitors are a specific class of epigenetic drugs that regulate cell gene expression without changing the actual gene sequence. Which means that although the tumor’s (cancer’s) genetic code is not changed by these drugs, how that genetic code is read and consequently used in various cell functions is disrupted. And thus far, for sarcomas, this disruption leads to inhibition of tumor growth in vitro and in vivo.[9]
The upfront pre-clinical work that cc-TDI is doing for SISU is a crucial part of the scientific process. Without crawling and walking first, a human clinical trial would not be possible.
And from Big Pharma’s perspective (the same companies that have the patent licenses on most of the drugs tested) this equates to “free” pre-clinical data (proof-of-concept), as it de-risks Big Pharma’s large investment to move forward with a specific drug for a specific disease in a clinical setting. By funding the early phases, these therapies have a higher likelihood of receiving a clinical trial and ultimately saving lives.
By preventing relapse for childhood Ewing’s Sarcoma survivors, we believe the implications of this study have the potential to make the biggest impact, in the shortest amount of time. And we are eternally grateful to our supporters. Thanks to you, the wheels of progress continue with the SISU Project at cc-TDI! We’d also like to thank our funding partners on this endeavor. We’re joining up with the 1 Million for Anna Foundation, and The Frank Family (parents to 6 yr old Ewing’s survivor Gus).
Currently, Dr. Keller, in conjunction with Junior Faculty Jinah Kim (PhD), are ramping up with supplies for Year 2 research and we will be sure to keep you posted on the exciting updates over the coming months. Until then, SISU-on!
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References:
Management of Recurrent Ewing Sarcoma: Challenges and Approaches. Van Mater and Wagner, 2019
Conditional Survival and Predictors of Late Death in Patients with Ewing Sarcoma. Davenport et al., 2016
Concise Review: Cancer Cells, Cancer Stem Cells, and Mesenchymal Stem Cells - Influence in Cancer Development. Papaccio et al., 2017.
Sarcoma Stem Cells: Do We Know What We are Looking for? Trucco and Loeb, 2012.
Developments in Continuous Therapy and Maintenance Treatment Approaches for Patients with Newly Diagnosed Multiple Myeloma. Dimopoulos et al., 2020.
Typical Treatment of Acute Lymphocytic Leukemia (ALL). American Cancer Society.
Recent Advances in Management of Pediatric Acute Lymphocytic Leukemia. Stary and Hrusak, 2016.
Exploiting Signaling Pathways and Immune Targets Beyond the Standard of Care for Ewing Sarcoma. Casey et al., 2019.
Therapeutic Applications of Histone Deacetylase Inhibitors in Sarcoma. Tang et al., 2017