Cancer researchers are developing a catalog of potential targets for novel treatments while they continue to identify genetic mutations powering different cancer subtypes.

Recently, the University of Michigan Comprehensive Cancer Center and Michigan Center for Translational Pathology (MCTP) completed a pilot investigation. The goal of the study was to solve the practical challenges researchers face in quickly and systematically sequencing genetic material from individuals suffering with advanced or treatment-resistant cancer so that they can be matched with existing clinical trials based on the biomarkers identified. Findings from the exploratory investigation, known as the Michigan Oncology Sequencing Project (MI-ONCOSEQ) are published in Science Translational Medicine.

Co-lead investigator Dr. Dan Robinson, a post-doctoral fellow at MCTP, explains:

“We’re talking about more than just examining a few genes where mutations are known to occur, or even about a hundred genes. We’re talking about the ability to sequence more than 20,000 genes and look not just for individual genetic mutations, but at combinations of mutations.”

The researchers discovered that identifying an individual’s “mutational landscape” offers a promising technique for determining which trials could help a patient the best.

Co-lead investigator Dr. Sameek Roychowdhury, a clinical lecturer in hematology and oncology at the U-M Medical School, says:

“High-throughput sequencing harnesses the latest technological advances to process millions of pieces of genetic information, allowing us to map a cancer’s genetic aberrations. Using this technique to identify biomarker-driven treatment options really opens the door for personalized oncology, but it also presents a number of logistical challenges, chief among them making the results available cost-effectively and in a clinically relevant timeframe.

A decade or two ago, this type of sequencing would have cost many millions or even billions of dollars, but the technology is advancing so rapidly, we’re now talking in terms of thousands – which makes widespread use a real possibility.”

Cancer can stem from an array of genetic changes, including additions, deletions, rearrangements and substitutions within the genetic code.

Roychowdhury, states:

“Different sequencing processes are required to find different types of alterations. But to be cost-effective, there must be a balancing act between a broad analysis and a deep analysis.”

The investigators started by examining the researchers’ sequencing approach on prostate cancer tumors that had been grown in mice. Later, the study enrolled two individuals in a clinical pilot: one patient with colorectal cancer and one with melanoma. For both participants, potential clinical trials were identified.

However, the investigators warn, not all individuals will match an existing study. Some with a certain mutation might be excluded as they have, say, prostate cancer, but a trial is only enrolling individuals with breast cancer. According to the investigators, this method also provides an opportunity to approach clinical trials in a novel way, moving from a tissue-specific focus toward genetic aberrations shared across different types of cancer.

They warn that enrolling in a trial does not guarantee the individual will benefit from the treatment.

Obstacles to extensive implementation include needing a multidisciplinary Sequencing Tumor Board to interpret the complex sequencing results, managing necessary computational resources, as well as a method for dealing with incidental genetic discoveries revealed by the sequencing, such as a risk for hemochromatosis, a genetic disorder in which the body absorbs too much iron.

It is vital to achieve a four-week turnaround time for results as that is the time period individuals are usually required to wait for unsuccessful treatments to leave their systems prior to starting a clinical trial.

Senior investigator Dr. Arul Chinnaiyan, director of MCTP, Howard Hughes Medical Institute Investigator, and S.P. Hicks Professor of Pathology at the U-M Medical School, says:

“Once some of the practical and technological hurdles are cleared, we envision an array of mutation and pathway-based trials for available targeted therapies, with eligibility based on molecular assessment. Moreover, if patients are treated with matching targeted therapies and develop secondary resistance, it could also help reveal the mechanisms of resistance and inform future trials for combination therapies.”

According to Chinnaiyan the work was only made possible by collaboration and teamwork. U-M physicians Dr. Moshe Talpaz, Dr. Stephen Gruber, and Dr. Kenneth Pienta played vital roles in the clinical implementation of this exploratory protocol, he notes.

The team hope that over the next 5 to 10 years this type of sequencing will become more widely available. Cancer patients are encouraged to speak to their doctors regarding clinical trial opportunities.

Written by Grace Rattue