Tuesday, June 16, 2015
The expansion of genomic information in lymphoma heralds a new era, where increasing knowledge of genetic lesions may help guide the selection of targeted cancer therapeutics. Sequencing data from the Cancer Genome Atlas reveals mutations in cellular processes common to all cancers, such as transcription factors/regulators, histone modifiers, genome integrity, receptor tyrosine kinase signaling, cell cycle, mitogen-activated protein kinases (MAPK) signaling, PI3K signaling, Wnt/β-catenin signaling, histones, ubiquitin-mediated proteolysis and splicing.
Traditionally, treatment for lymphoma has involved multi-agent chemotherapy, followed by stem cell transplantation for relapse. In the modern age of genomics, we can discretely classify lymphomas based on mutational drivers. In diffuse large B cell lymphoma, driving mutations occur in epigenetic modifiers, immune escape, chronic B cell receptor signaling, deregulated survival signaling, and disruption of terminal differentiation.
Optimizing Patient Selection
We now hope to create clinical trials using the mechanism-based identification of novel agents, optimizing response by employing a combination of genomic and proteonomic tests to select patients.
One of our first clinical trials using this approach is a phase II trial with mocetinostat, an HDAC inhibitor (HDACi), for patients who harbor CREBBP/EP300 mutations in DLBCL and FL (NCT02282358). Mutant CREBBP and EP300 proteins are deficient in acetylating BCL6 and p53, leading to the constitutive activation of the oncoprotein and decreased p53 tumor suppressor activity. The balance between the activities of these two genes is critical for the regulation of DNA damage responses in mature germinal center cells during immunoglobulin gene remodeling. The consequences of BCL6 activity overriding p53 would be an increased tolerance for DNA damage in the context of diminished apoptotic and cell cycle arrest responses. The use of HDAC inhibitors in this HAT mutated population may contribute to re-establishing physiologic acetylation levels sensitizing the lymphoma to cellular apoptosis and cell cycle arrest. These observations raise hopes that CREBBP/EP300 genetic alterations may serve as genetic biomarkers to predict response to HDACi.
This trial is among other biomarker-driven trials in lymphoma, and the results will build support of genomic or biomarker-based patient selection for clinical trials, in lieu of traditional patient selection by histology.Back to top
Focusing on Shared Genomic Alterations
We are currently applying the next generation of targeted genomic sequencing strategies for our patients at MSK. The application of a comprehensive genomic sequencing assay provides an opportunity to both describe the spectrum and compare the incidence of genetic alterations across different lymphoma subtypes. Preliminary data from two abstracts presented at the American Society of Hematology (ASH) Annual Meeting in 2014 suggest the vast majority of patients have one or more genomic alterations linked to approved agents or clinical trials. This data will facilitate the design of clinical trials by providing the opportunity to select patients based on shared genomic alterations, rather than lymphoma subtype.Back to top
To refer a patient for targeted genomic sequencing, please call our lymphoma service referral line at 646-497-9137. To inquire about the mocetinostat clinical trial for a DLBCL or FL patient with CREBBP/EP300 genomic alteration, please contact Dr. Andrew Zelenetz at 212-639-2656.
Batlevi et al, “Identification of Actionable Genomic Alterations Across Different Lymphoma Histologies Using a Comprehensive Next Generation Genomic Sequencing Clinical Assay,” ASH 2014, Abstract 3000. http://goo.gl/Raxxjx
Intlekofter et al, “Genomic Profiling Combining DNA and RNA Analysis of 112 Formalin-Fixed Paraffin-Embedded Diffuse Large B Cell Lymphoma Specimens Identifies a High Frequency of Clinically Relevant Genomic Alterations,” ASH 2014, Abstract 704. http://goo.gl/EZKwXyBack to top