Taking Down an Ogre
Hemangiosarcoma is arguably the worst cancer seen in dogs. It is a cancer that can develop in any part of the body, has a high propensity to spread to other organs, and is not effectively treated with existing therapy. Ethos Discovery began its attack on hemangiosarcoma through the first-ever, prospective, nationwide, multicenter study of canine hemangiosarcoma (CHAMP Study). CHAMP taught us that hemangiosarcoma is not a single cancer, but rather at least four cancer subsets, characterized by several genomic alterations. From our unique perspective as cancer biologists and veterinary oncologists, we view these distinct cancer entities through the optics of novel therapeutics that may be reasonably applied to the identified disease subsets. In addition, our preliminary data has demonstrated the presence of mutated cancer DNA in the blood of dogs with hemangiosarcoma (i.e. liquid biopsy, which has the potential for aiding in diagnosis and treatment monitoring).
Ethos Discovery Has a Plan
These new data and the expertise of our multidisciplinary team allow us to now deliver a highly advanced clinical trial program in the field of precision medicine through an umbrella study design. Although it is alluring to believe that we can simply match drugs to individual patients as part of a precision medicine approach to oncology, this has been surprisingly challenging in most human cancers. We can learn from the missteps in the human field. Accordingly, our Plan in Precision Medicine, seeks to address challenges through our post hoc umbrella study in hemangiosarcoma (Ethos-PUSH; Precision Medicine Umbrella Study for Hemangiosarcoma).
An umbrella study segments patients with a given cancer (such as hemangiosarcoma) into molecular subsets. We plan on conducting a modified approach to the Umbrella design by randomly assigning dogs to drugs that were selected based on our current understanding of the biology of hemangiosarcoma, and then asking which combination of drugs and disease subsets delivers the best outcomes, post hoc. This will enable us to associate drug response with molecular biomarkers and understand which therapeutics best target alterations of that patient subset.
The success of precision medicine in the field of oncology has been shown to require an understanding of a drug and its interaction with a molecular target in the disease of interest (referred to as “molecular context”). Indeed, a lack of understanding of drug-target context may explain some of the recent failures to demonstrate the therapeutic value of precision medicine in humans, beyond the visible success in lung cancer. Our new understanding of the genomics of hemangiosarcoma provides the basis to evaluate the role of drugs that may target altered hemangiosarcoma genes as part of our plan to deliver curative outcomes for this disease. Beyond cancer genomics and precision medicine our plan seeks to make prospective controlled studies in hemangiosarcoma available to as many pet families as possible and in so doing, we expect iterative improvements in long term outcomes to be delivered to patients. This stepwise approach to delivering curative outcomes has been successfully used by the Children’s Oncology Group in their care of children with leukemia. Indeed, the success in the conversion of childhood leukemia from a commonly fatal diagnosis only 30 years ago to a diagnosis associated with a high likelihood of cure today, did not occur from a single ”home run”, but by successive improvements in outcome delivered by prospective trials.
This approach now represents a road map in our Ethos Discovery approach to hemangiosarcoma in dogs. The key features of this plan that now constitute our road map include:
- An aspiration to include all eligible patients in the US into prospective trials over the next 5 years.
- To be agnostic of the source of new ideas and welcome collaboration from the best new ideas.
- An understanding that no single drug or approach will be the answer.
- To design prospective studies to allow both informative failures and unexpected successes to fuel future iterations.
Our Plan is Agnostic to the Source of Good Ideas
Ethos-PUSH has a defined trial design, a rationale for drug evaluation; however both the drugs and the correlative science (diagnostics, prognostics, theranostics) have been included without a “founder bias” from Ethos Discovery, i.e., we do not seek to advance any specific approach, but rather are solely focused on the desired outcome (i.e. curative outcome in canine hemangiosarcoma). We are agnostic to the source of good ideas.
In addition to the therapeutic trial, Ethos-PUSH includes several correlative science objectives:
- Tissue based prognostic markers to allow segmentation of patients (i.e. STAMP: Specialized Test for Assessment of Molecular Prognosis.
- Liquid Biopsy Development-exploring both genomic and protein biomarkers to allow diagnosis, prognosis, and therapeutic monitoring.
- Biological model development including hemangiosarcoma cell lines and canine patient derived mouse models.
- Cross-species comparative genomics to allow acceleration of research into the “drivers” of hemangiosarcoma/angiosarcoma biology, through parallel studies in the dog and human.
- Development of specialized approaches for hemangiosarcoma sample collection to manage the disease heterogeneity.
- Moving beyond the genome to understand super-enhancer biology in canine hemangiosarcoma.
In addition to the above planned correlative science, this study will serve as the largest collection of canine hemangiosarcoma biospecimens in the world. These biospecimens will be made available to independent collaborators with the goal of further understanding the genomics, epigenomics, and biology of hemangiosarcoma and guide the optimal management of patients.