Dana-Farber Cancer Institute Archives - Page 2 of 2

2017

Scholar Grant

Dr. Rani E George

Boston, MA

Despite substantial therapeutic advances, the survival rate of high-risk neuroblastoma (NB) patients remains dismal, with about half experiencing fatal relapse. Mutations in the ALK receptor tyrosine kinase (RTK) gene are present in 10% of all NB cases, and have been validated as tractable therapeutic targets in this disease, leading to clinical trials with the ALK inhibitors crizotinib and ceritinib. To date, pediatric Phase 1 testing has been completed for crizotinib, resulting in its planned incorporation into the new Children’s Oncology Group trial for high-risk NB patients with tumor ALK mutations. However, as with all targeted therapy, the development of resistance is almost inevitable even when combined with chemotherapy, and the underlying mechanisms have not been elucidated. Here, we propose to identify the causes of resistance to ALK inhibitors in NB. In preliminary studies we identified that NB cells develop different resistance mechanisms to ALK inhibitors based on the presence of concomitant MYCN amplification. These involve the use of alternative pathways to enable cell growth and survival: (I) activation of another kinase, AXL, leading to activation of downstream signaling in cells with nonamplified MYCN, and (ii) epigenetic modifications with enhanced sensitivity to BET bromodomain inhibition in cells expressing amplified MYCN.

In Aim 1, we will devise strategies to overcome resistance to ceritinib in NB cells expressing ALK mutation, with or without associated MYCN amplification.
In Aim 2, we will identify and dissect mechanisms of acquired resistance to crizotinib in NB cells exposed to combination chemotherapy.

The studies proposed here will provide insight into the mechanisms of resistance to ALK inhibition and explore the potential of combination targeted therapy to treat or even prevent resistance so as to enable the appropriate selection of patients likely to respond to this treatment strategy.

2017

Young Investigator

Dr. Brenton G. Mar

Boston, MA

Targeting Histone 3 Lysine 36 Methylation in Pediatric Leukemia

Despite substantial improvements in the treatment of pediatric acute lymphoblastic leukemia (ALL), relapsed ALL remains the most common cause of cancer related death in children. Patients with relapsed ALL have substantially worse outcomes, reflecting the acquisition of chemotherapy resistance. We recently found that mutations in epigenetic regulators, proteins that modify DNA or its larger structures, are recurrently gained in relapsed ALL. Among these mutated epigenetic regulators, we identified novel mutations in SETD2, which lead to resistance to the commonly used chemotherapy agent cytarabine. Including mutations in another similar regulator, WHSC1, alterations in this epigenetic pathway occur in 10% of pediatric ALL, and our preliminary data show they are associated with substantially worse outcomes for these patients.

Discovering and validating novel prognostic markers in pediatric ALL has been critical to progress we have made so far in ALL by identifying patients at high risk for relapse and intensifying or providing alternative treatments for them. In this proposal, I will characterize a large cohort of uniformly treated ALL patients for mutations in SETD2 and WHSC1 and determine their value in predicting relapse. Patients with these mutations could be considered for upstaging to additional chemotherapy or alternative non-DNA damaging chemotherapy in future trials.

In addition, this proposal seeks to evaluate a novel strategy of treating leukemias with these mutations through epigenetic modulation. This proposal will validate a specific strategy of targeting these mutations and define a set of leukemia models, both in cell culture and in patient derived leukemia animal models, to test future clinical drug candidates. A number of drug companies are developing pharmaceutical grade selective small molecule inhibitors of this pathway, and exciting opportunities will exist to translate these into the clinic in the future.

2014

Scholar Grant

Dr. Kimberly Stegmaier

Boston, MA

A new class of drugs targeting chromatin regulating proteins has entered clinical trials for adults with cancer. These chromatin regulating proteins control the “marks” on DNA and the histone proteins around which DNA is wound. Our laboratory discovered that the pediatric solid tumor neuroblastoma was one of the most sensitive diseases to BET bromodomain inhibitors, a new type of chromatin regulating drug. We also discovered that amplification of the gene MYCN, a frequent and poor-prognostic event in neuroblastoma and medulloblastoma, was the most predictive marker of sensitivity to BET bromodomain inhibitors. Our team will conduct a clinical trial to test a BET bromodomain inhibitor in children with relapsed/refractory pediatric solid tumors (including neuroblastoma), medulloblastoma, and lymphoma. One critical aspect of targeted therapy testing is to validate highly effective inhibition of the target of interest. All too often when there are no responses seen in a trial, one is left wondering whether the problem is a bad drug or a bad protein target. The study of target inhibition in pediatrics is further complicated by the difficulty/ethical considerations in obtaining multiple tissue biopsies in young children. A second critical issue is the identification of effective biomarkers that predict response to a targeted drug class. In this proposal, we will perform the essential correlative biology studies for the clinical trial to determine whether we are effectively inhibiting BET bromodomains and to identify biomarkers of response to this promising new drug class. Second, we will develop an assay with the potential to transform targeted therapy development for children with neuroblastoma by harvesting tumor cells from the blood. A circulating tumor cell assay would enable serial sampling of tumor cells from these children for measurement of response to therapy, target inhibition, minimal residual disease, and drug resistance mechanisms all with a simple blood draw.