Fred Hutchinson Cancer Research Center Archives

2019

Scholar Grant

Vivian Oehler

Seattle, WA

Title: Optimizing risk stratification and targeting therapy resistance in pediatric acute myeloid leukemia patients using microRNA-based approaches

Executive Summary:
Acute myeloid leukemia (AML) is a highly lethal cancer. Although survival rates have improved over the last decades, about half of young AML patients relapse, even after the most intensive available treatments. Furthermore, today’s strategies to treat relapse are often unsuccessful and have serious side effects. Safer, more effective therapies are urgently needed. In the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program, investigators have applied the first, highly comprehensive approach to identify the molecular alterations that contribute to therapy resistance and relapse in children and young adults with AML. The overarching goal is to advance new diagnostics and novel individualized treatments that will improve patient outcomes, including a focus on small “micro RNA” (miRNA) molecules that negatively regulate specific gene expression. Dr. Vivian Oehler’s TARGET discovery studies showed that miRNAs can be used as diagnostic ‘biomarkers’ to identify patients for whom standard chemotherapy is likely to fail. She and her collaborator, Dr. Soheil Meshinchi, now propose studies in Aim 1 to further validate these biomarkers in an independent group of 400 patients. The goals are to:
– optimize a 36-miRNA panel that they have already developed and corroborate its predictive power
– develop an assay that can translate easily to clinical application.
In Aim 2 studies Dr. Oehler in collaboration with Dr. Marcin Kortylewski will learn how specific miRNAs promote leukemia evolution and therapy resistance.
The goals are to:
– identify the molecular processes through which the different miRNAs act, including effects on leukemia cell proliferation, metabolism and survival
– use mouse models to learn precisely how specific miRNAs might be used therapeutically and/or which drugs can reverse their leukemia-supportive effects.
The proposed studies will thereby help classify patients who will benefit from alternative treatment strategies, identify new therapeutic targets and advance promising interventions in pediatric leukemia.

2017

Scholar Grant

Dr. Cecilia Yeung

Seattle, WA

Acute leukemia (AL) is the most common cancer in children with over 5000 newly diagnosed

cases in the US in 2016. Many pediatric ALs (PAL) have recurrent chromosomal rearrangements leading to fusion genes that, upon detection, allow not only for confirmation of the diagnosis but also provide prognostic information and can guide therapy for the patient’s disease. However, studies currently available to detect these chromosomal rearrangements are costly and slow, leading to delays in diagnosis -notably delays that are strongly suggested as contributing factors to early death in patients with AL. More work is needed to maximize their utility in a clinical setting.

The primary goal of this study is to alter the clinical “standard of care” by providing physicians with the technology required to diagnosis at an earlier stage and better treat pediatric patients with personalized medicine targeting their specific gene rearrangements.

Outcome: A low-cost, off-the-shelf diagnostic test for PAL utilizing iPCR technology that, when paired with a disposable handheld device usable at room temperature, provides easy-to-read results similar to that seen in common over-the-counter pregnancy tests.

The Specific Aims of this project are:
SA #1. Develop a novel, multi-targeted, diagnostic test for detection of translocations in pediatric acute leukemia;
SA #2. Build a multiplexed lateral flow device (similar to a pregnancy test strip) to host SA #1 technology.
SA #3. Pair SA #1 and #2 in a portable device for molecular characterization of the PALs at the bedside.
This work translates to life-saving benefits for PAL patients in a clinical setting by:
i) Facilitating real-time clinical decision-making in time-critical situations,
ii) Reducing the number and length of hospital stays,
iii) Increasing patient satisfaction through personalization of treatment options, and
iv) Reducing the risk of human error in molecular testing
No FDA-approved multiplex iPCR diagnostic tests are currently available on the market.

2014

Scholar Grant

Dr. Brandon Hadland

Seattle, WA

Hematopoietic stem cell transplants are used to treat children with inherited disorders of the bone marrow that can lead to leukemia. Gene therapy holds the promise of improved cures for these patients by correcting defects in their own stem cells before leukemia develops, but making gene therapy a reality will require better methods to expand patient-specific stem cells outside the body so that they can be transplanted back to patients once corrected. The goal of this research is to develop methods to generate and expand hematopoietic stem cells from novel sources, such as patient-specific induced pluripotent stem cells, to facilitate gene therapy for treatment of inherited marrow failure/leukemia predisposition, as well as to provide a new source of hematopoietic stem cells for additional applications for treatment and support of pediatric cancer patients.