The Oncology Research Information and Exchange Network® (ORIEN) is a first-of-its-kind alliance of the nation’s top cancer centers with a common goal—to revolutionize cancer care. Therapies for cancer have traditionally been targeted to “average” populations, consisting of treatments such as radiation therapy, chemotherapy, and surgery. However, as researchers begin to understand the cellular DNA mutations that drive the development and spread of specific cancers, it has become clear that there is nothing average about any patient’s cancer.

Powered by M2GEN’s data and molecular pipeline analytical services, ORIEN is providing researchers, biopharmaceutical companies, and other key stakeholders access to robust, standardized molecular and longitudinal clinical data. This promotes seamless collaboration and accelerates novel discoveries. The culmination of M2GEN’s efforts is the ORIEN Avatar® program, which creates a broad view of the cancer landscape by providing panoptic, multi-modality, highly curated data.

There is no one-size-fits-all approach to cancer care. By unraveling the many mysteries around the genetic changes that underpin a specific cancer’s development and response to treatments, researchers are developing more personalized and effective approaches, such as immunotherapy, that are targeted to individual genetic profiles.

Q&A With an Expert on the Benefits of ORIEN Membership

The Markey Cancer Center joined the ORIEN alliance in 2017, implementing the patented Total Cancer Care® (TCC) protocol to collect genetic and clinical data from consenting patients with cancer. Jill Kolesar, PharmD, MS, a university research professor at the University of Kentucky and administrative director of the Precision Medicine Clinic at the UK Markey Cancer Center, took the time to share her experiences with ORIEN and M2GEN.

Q: Can you please provide an overview of your experience with ORIEN membership and how it has helped to advance your research?

A: We have recruited about 5,500 patients to TCC since joining in 2017, including approximately 1,800 who are included in Avatar. Using Avatar data, we have identified interesting genomic signatures in our Kentucky population. We have also demonstrated that individuals living in rural, underserved, and economically disadvantaged areas are just as likely to enroll in genomic studies like Total Cancer Care as their affluent, urban-dwelling, and predominantly white counterparts.

Q: Who can benefit from using ORIEN data? What value can they expect to take from membership that they might not be able to find with other solutions?

A: Cancer researchers and patients both benefit from using ORIEN data. Rural and underserved populations are not usually enrolled in trials or genomic studies. Since most new drug development in oncology is targeted to specific mutations, not understanding the mutations underlying a malignancy results in drugs being developed that are not as relevant for these populations.

Cancer researchers benefit by having a fully curated clinical and genomic data set for research, with the option of re-contacting patients for future research.

Dr. Kolesar elaborated on the significance of collecting clinical and molecular data from underserved communities.

“Other data-sharing networks are primarily at very large cancer centers on the coasts,” Dr. Kolesar said. “One of the things we’ve been able to do at Markey as a tertiary referral center for most of Kentucky is enroll patients from rural and underserved areas and get their genomics into a large database.”

Factors such as race, ethnicity, and environment contribute significantly to genetic mutations that can cause cancer. By creating a platform to incorporate a diverse population over larger geographic areas into genomic datasets, ORIEN and M2GEN are powering research that will drive the development of more effective therapies for previously underserved patients. As Dr. Kolesar states, “We are already seeing that there are major differences between mutations in our population and what we see in other large databases. If patients with different genomics aren’t represented in these databases, there won’t be new drug development targeting the types of cancers in our population.”

Q: How are ORIEN and M2GEN evolving? What do members have to look forward to in the future?

A: M2GEN is expanding numbers and diversity of sequenced patients and enabling members to ask bigger questions across a larger population.

Indeed, ORIEN and M2GEN have led the charge in empowering researchers to advance precision cancer care by creating one of the most comprehensive registries of consenting cancer patients in the world. As the TCC protocol is implemented at more cancer centers and patient participation increases, the data available will become increasingly diverse and robust, enabling researchers to glean valuable insights into everything from actionable cancer biomarkers to pharmacogenomics.

The Power of ORIEN Membership & M2GEN Data: A Case Study on DACH1 Mutations

In 2020, Dr. Kolesar was the principal investigator on a study out of the Markey Cancer Center (MCC): Riggs MJ, Lin N, Wang C, Piecoro DW, Miller RW, Hampton OA, Rao M, Ueland FR, Kolesar JM. “DACH1 Mutation Frequency in Endometrial Cancer is Associated with High Tumor Mutation Burden.” PLoS One. 2020 Dec 30;15(12):e0244558.

The study underscores the benefits of ORIEN membership as well as the potential for data from M2GEN to move precision cancer care research forward.

DACH1 is a transcriptional repressor and tumor suppressor gene that is frequently mutated in melanoma as well as bladder and prostate cancer. Using the ORIEN Avatar database, the MCC study set out to determine the frequency of DACH1 mutations in 65 women with endometrial cancer being treated at MCC. According to Dr. Kolesar, “M2GEN helped us develop our cohorts for the DACH1 study. In addition to performing the sequencing and bioinformatics pipelines, M2GEN was instrumental in helping us set up the DACH1 mutant versus wild-type cohorts.”

The MCC study showed that DACH1 mutations are prevalent in Kentucky women with endometrial cancer, a discovery that has potentially significant implications on the future development of precision cancer therapies, particularly for patients in rural communities. Additionally, there was another study conducted by Dr. Kolesar’s team: Riggs MJ, Huang B, Chen Q, Bocklage T, Schuh MR, Poi M, Villano JL, Cavnar MJ, Arnold SM, Miller RW, Ueland FR, Kolesar JM. “Factors Predicting Participation in the Prospective Genomic Sequencing Study, Total Cancer Care (TCC), in Kentucky.” J Rural Health; 2020 Jul 6;10.1111/jrh.12492. The team provided evidence that patients in rural areas were just as likely to participate in cancer studies as individuals from more affluent populations that are currently overrepresented in genomic databases.

“Our consent rate is over 90%, which is very high,” Dr. Kolesar said. “This is a study that isn’t necessarily going to benefit the patients directly, but we explain to them that it will help us learn more about cancer and benefit patients in the future. I think it says a lot about the people of Kentucky and their willingness to help others.”

By finding evidence of the elevated frequency of DACH1 mutations in Kentucky women with endometrial cancer, the MCC study also highlights that cellular DNA mutations can differ significantly based on population. Dr. Kolesar emphasized that research into population-level differences in cancer genomics is still in its infancy, and further study is needed.

Perhaps most importantly, the results of the MCC study have the potential to drive new drug development that helps cancer patients with DACH1 mutations in the future.

“If you have a DACH1 mutation, you’re more likely to have a high tumor mutation burden,” Dr. Kolesar said. “Having a high tumor mutation burden makes you a candidate for immunotherapy.”

MCC is already in discussion with biopharmaceutical companies to design clinical trials that would test the efficacy of immunotherapy in patients with DACH1 mutations. However, as is the case with any new cancer therapy, research and development will be a time- and resource-intensive endeavor. MCC will first need to expand the study and validate its findings.

“We have to see if these results hold up across different populations,” said Dr. Kolesar. “If they do, the next step would be to establish DACH1 as a cancer biomarker to target with immunotherapy.”

M2GEN will be instrumental in this effort, as the next phase is to use ORIEN Avatar data to include all endometrial cancer patients who are enrolled through the Total Cancer Care protocol and have sequencing data available. A combination of fully annotated whole exome and transcriptome sequencing data with more than 600 elements of clinical data from hundreds of thousands of consenting patients makes the Avatar platform uniquely suited to yield accurate, efficient analysis and validation.

Empowering the Development of Precision Cancer Treatment Now & in the Future

As the study on DACH1 mutations at Markey Cancer Center shows, research into cancer-causing genetic mutations is beginning to bear fruit. At M2GEN, we are proud to provide researchers with the tools they need to identify these unique genetic signatures and better understand how to target them with precision treatments. Contact M2GEN today to learn more about the ORIEN Avatar platform as well as our custom, oncology-focused bioinformatics tools and services.

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