The 2015 annual AMP meeting opened Novemeber 5th in Austin TX, with a presentation by Dr Brian Druker titled “Imatinib as a Paradigm of Targeted Cancer Therapies.” This year’s recipient of the AMP Award for Excellence in Molecular Diagnostics, Dr Druker highlighted the importance of identifying patients through biomarkers and matching therapies to the patient. This theme continued through many of the presentations, posters and vendor exhibits the importance of providing physicians actionable results for patient care and therapeutics. Molecular diagnostics are critical to any discussion on precision or personalized medicine.
There were several presentations on umbrella and basket trials which cohort patients not strictly by disease or cancer type, but by biomarkers. In basket trials, lung, colorectal and breast cancer patients with specific somatic mutations in activating genes are all candidates for a specific drug trial. In the umbrella trials, breast cancer patients may be grouped into different therapeutic arms of the trial based upon their biomarkers and expected responses to multiple treatments from collaborating pharmaceutical manufacturers. For those in the diagnostics field, this means supporting the trials through better sample conservation to provide accurate and timely results across platforms and methodologies. Liquid biopsies such as blood, urine, cerebral spinal fluid, saliva or other non-invasive fluid samples may contain biomarkers shed from malignant or diseased cells. These are easily obtained samples that allow detection of specific nucleic acid and protein markers that can provide longitudinal data over the course of treatment(s). Several speakers highlighted the extreme importance of both prospective and retrospective patient sample collection for current and future clinical trial. Clinical trial design should consider the requirements for not only the ongoing trial but also potential additional testing. These are both critical to patient care and therapeutic intervention.
Oncology presentations highlighted important immunotherapies including anti-PD-1 drugs (nivolumab) for solid tumors, and Chimeric Antigen Receptor T-cells (CAR) for B-cell chronic lymphocytic leukemia. The successful response to PD-1 inhibitors depends upon the patient’s tumor and PDL-1 expression and provides an additional option to patients who have not responded to other therapies. CAR therapy has met with significant success in B-cell malignances with limited efficacy in solid tumors. Dr Michael Milone emphasized the importance of preclinical models that matched patient’s immune responsiveness when targeting CAR T-cells to CD19. Genetic variants in CD19 have been identified in patients who did not respond to CAR therapy, once again demonstrating the importance of biomarker screening.
Epigenetic changes in aberrant DNA methylation is an area of growing interest in cancer biology research and translation as potential biomarkers for disease identification and monitoring. For example, in T-cell acute lymphocytic leukemia/lymphoma (T-ALL), mutations in DNMT3A have been observed in >20% of patients. In normal cells, DNMT3A is a potent tumor suppressor maintaining normal cell methylation patterns. Mutations that compromise DNMT3A function, however, negate its ability to suppress otherwise tumor activating genes. Self-renewal of otherwise normal DNMT3A mutant stem cells can present significant difficulties in the long-term treatment of ALL patients. DNMT3A mutations may attribute to clonal dominance stem cells in aging populations and compromised tumor suppressor capabilities. These epigenomic alterations are not just confined to the cancer space, but are found in other diseases as well.
The importance to our microbiome and its influence on the immune response in health and disease was a topic of growing interest at the AMP meeting. Understanding the basic interplay between immune health and commensal organisms, inflammatory processes and infectious diseases, as well as disease and neoplasm are all critical to the continued advancement of precision medicine. The bacteria in the normal gut flora can be used to group human beings. In turn, these groups can be associated with increased risk of adverse health events. Specifically, microbial species imbalance or dybiosis can increase the human host risk of obesity, IBD and infectious disease.
In the future patients may not only have a human genomic sequence, but a microbiome sequence and an epigenetic profile for physicians to assess. Stay tuned-next year will be even more interesting.