Applying Precision Genomics in Biopharma Drug Development
Onconova Therapeutics, Inc. is a biopharmaceutical company dedicated to discovering and developing novel products to treat cancer. Specifically, Onconova focus on Myelodysplastic Syndrome (MDS). Recently, the company announced a collaboration with Mission Bio to utilize the Mission Bio TapestriⓇ Platform to conduct targeted single-cell DNA analysis for the study of Onconova's novel cancer therapy, Rigosertib.
Mission Bio are pioneers in targeted single-cell DNA analysis and precision genomics. Using the TapestriⓇ Platform, the collaboration will study cancer subclones and co-occurring cancer mutations at the single-cell level, offering a precise way to measure therapy response and disease progression. Technology Networks spoke with Darrin Crisitello, CCO of Mission Bio, to find out more.
Laura Lansdowne (LL): Can you tell us more about Myelodysplastic Syndromes (MDS)?
Darrin Crisitello (DC): Myelodysplastic syndromes (MDS) are conditions that can occur when the blood-forming cells in the bone marrow become dysfunctional and thus produce an inadequate number of circulating blood cells. They are frequently associated with the presence of blasts or leukemic cells in the marrow.This leads to low numbers of one or more types of circulating blood cells, and to the need for blood transfusions. In MDS, some of the cells in the bone marrow are abnormal (dysplastic) and may have genetic abnormalities associated with them. Different cell types can be affected, although the most common finding in MDS is a shortage of red blood cells (anemia). Patients with higher-risk MDS may progress to the development of acute leukemia.
LL: How do precision biomarkers reduce the time and costs associated with the drug development cycle?
DC: In identifying precision biomarkers, researchers have the level of insight necessary to monitor the evolution of cancer cells, revealing how specific mutations drive disease progression or therapy resistance in patients. The problem is, broad-based sequencing methods lack the sensitivity to identify such markers.
With Mission Bio’s Tapestri Platform, researchers can uniquely detect rare cancer subclones and co-occurring cancer mutations at the single-cell level, offering a precise way to measure therapy response and disease progression. It delivers actionable insights with precision, speed, and scale, sequencing 10,000 cells per run in up to 1/100th of the time of conventional single-cell analysis, and with 50 times greater sensitivity than traditional bulk sequencing techniques. With this level of insight, researchers can better support the advancement of new therapies to the clinic.
Molly Campbell (MC): What insights can single-cell DNA analysis offer during the clinical trial process?
DC: Single-cell DNA analysis provides insight into disease origins and paths of progression and can allow researchers to identifying those treatment-emergent mutations missed by traditional sequencing methods. With insight at the single-cell level, one can monitor the evolution of the disease in response to a particular targeted therapy, allowing for researchers to develop even more impactful treatments.
There is keen interest in improving the identification of residual cancer cells that remain after treatment to provide more specific information about treatment response and remission durability. A more sensitive test for minimal residual disease (MRD), which is possible through single-cell genomics, has great potential to streamline clinical trials and help providers manage their patients’ care more effectively.
LL: The investigational new drug “rigosertib” is currently undergoing clinical investigation. Can you tell us more about its clinical progress, the specific indication it has been developed for, and its mechanism of action?
DC: Ras proteins control cell growth, and mutation of this protein can lead to cancer in affected individuals. Ras is mutated in over 30 percent of patients with the disease, making this cancer-causing gene one of the most sought after for treatment. Onconova developed rigosertib to combat this mutation -- a first-in-class small molecule Ras imitator, the drug blocks the activation of Ras effector proteins, thus inhibiting disease progression.
Rigosertib is on track to complete stage III of clinical trials later this year, a pivotal milestone in its advancement toward the clinic. The trial, known as INSPIRE, and is an open label, randomized, controlled, international study designed to determine the efficacy, safety and tolerability of single agent intravenous (IV) rigosertib to treat second-line higher-risk MDS patients.
The trial includes patients under the age of 82 who have progressed on, relapsed, or failed to respond to previous treatment with hypomethylating agent (HMA) therapy within nine cycles over the course of one year after initiation of HMA therapy. Patients are randomized to receive either rigosertib with best supportive care, or the physician’s choice of therapy with best supportive care. The primary endpoint of the study is the sequential analysis of overall survival of all randomized patients in the intent-to-treat population, and the International Prognostic Scoring System - Revised (IPSS-R) Very High-Risk subgroup.
Based on the promising survival signal observed by the Independent Data Monitoring Committee at interim analysis in early 2018, the Committee recommended that the trial continue with an expansion in enrollment to 360 patients based on a pre-planned sample size re-estimation.
MC: How will Mission Bio’s Tapestri® Platform for targeted single-cell DNA analysis be used to study this novel cancer therapy? What specific benefits does it offer compared to current available methods?
DC: Current methods for analyzing cancer mutations largely rely on a technique known as next-generation sequencing (NGS), which processes DNA in bulk and relies on sample averages. But this method misses the underlying genetic diversity and overlooks the rare cells that drive the disease.
With the Mission Bio Tapestri Platform, researchers can detect rare cancer subclones and co-occurring cancer mutations at the single-cell level, offering a precise way to measure therapy response and disease progression. Supporting the pharma and biopharma industries through clinical trials and commercialization continues to be a focus for Mission Bio.
Tapestri’s unique sensitivity empowers Onocnova’s research and development to monitor the evolution of the disease in response to targeted therapy, ultimately revealing how specific mutations drove subsequent therapy resistance or progression in patients. These studies have the potential to make a meaningful difference in the lives of patients in need.
MC: Are there any challenges associated with adopting single-cell DNA analysis in this context?
DC: The Tapestri Platform can be pretty easily adopted into any lab already running Illumina NGS workflows, as the Tapestri Plaform is compatible with NextSeq, HiSeqs and NovaSeqs. Also, Tapestri Pipeline and Insights Software provide pushbutton analysis workflows for helping to interpret this novel data type.
Darrin Crisitello was speaking with Laura Lansdowne and Molly Campbell, Science Writers, Technology Networks.