By Todd M. Cooper, DO
Advances in cancer can be attributed to a number of factors including progressive intensification of therapy, improved supportive care, and excellent participation in cooperative group clinical trials. However, there is still a great deal of work to be done, especially for patients diagnosed with high-risk malignancies. Improved understanding of cancer genomics, along with advancing knowledge of aberrant signal transduction pathways, can potentially lead to even greater survival of those diagnosed with malignancies.
The three presentations delivered yesterday in the Scientific Committee Session on Novel Targeted Therapies in Malignant and Nonmalignant Blood Disorders summarize exciting breakthroughs in the areas of genomic technology, understanding of the Ras pathway, and new signal transduction inhibitors in lympho-proliferative diseases (LPDs).
Dr. Cheryl Willman described the use of genomic technology to identify novel genetic abnormalities and therapeutic targets in pediatric acute lymphoblastic leukemia (ALL). The identification of molecular subtypes of ALL that correlate with treatment outcomes allows physicians to identify patients with low-, intermediate-, and high-risk disease. However, in the majority of patients, the underlying genetic abnormalities have yet to be identified. She described the implementation of comprehensive genomic technologies that have resulted in the identification of novel underlying genetic abnormalities and therapeutic targets in high-risk ALL. In particular, implementation of these methods led to the discovery of molecular classifiers predictive of relapse-free survival and minimal residual disease at the end of induction. Novel genetic abnormalities and genes that could represent novel therapeutic targets were identified among clusters of these molecular classifiers. These studies demonstrated that new molecular classifiers can identify prognostic groups within high-risk ALL, improving the ability to prospectively identify children who will respond or be resistant to current therapies.
Dr. Kevin Shannon, in his presentation titled “Biology, Therapy, and Resistance of Myeloid Malignancies Initiated by Hyperactive Ras,” described the importance of this signal transduction pathway in leukemogenesis. He described the prevalence of oncogenic RAS mutations and other genetic mechanisms that lead to hyperactive RAS, making it an attractive therapeutic target. He has created novel tumor models using strains of mice carrying mutant alleles of NF1, as well as oncogenic Nras and Kras. Using retroviral insertional mutagenesis, he has been able to identify cooperating mutations that may induce progression from myeloproliferative disorders to acute myeloid leukemia. These models are important in testing the response of targeted agents and identifying genes that modulate mechanisms of resistance.
The last presenter, Dr. Stephan Grupp, in his presentation titled “Signal Transduction Inhibitors in Lymphoproliferative Diseases (LPDs),” described the potential for targeted therapies for both malignant and nonmalignant hematologic disorders. In particular, he focused on ALL and autoimmune lymphoproliferative syndrome (ALPS) and murine models of these disorders that identify potential targets for therapy. These models, along with in vitro bone marrow stromal cell culture systems and primary ALL xenografts, serve as a foundation for identification of relevant targets in the mTOR, IL-7, and Notch pathways. Dr. Grupp described clinical trials utilizing inhibitors of these targets in patients with ALL and ALPS.
Dr. Cooper indicated no relevant conflicts of interest.
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