Preventing skin cancer with a DNA-repair enzyme. Understanding how microRNAs modify cancer immunity. Using zebrafish embryos to rapidly assess toxicity of anticancer drug combinations. These are some of the ideas researchers are pursuing with the latest round of Knight Cancer Institute pilot project grants.
The $50,000 awards help early career and senior investigators generate preliminary data to enable funding from external, peer-reviewed sources such as the National Institutes of Health. Selection criteria encourage inter-disciplinary research in which investigators from disparate scientific areas collaborate to bring unique approaches to the cancer problem. The awards are made possible by support from The Hillcrest Committee, the Albert and Elaine Borchard Foundation, and the Knight Cancer Institute’s NCI Cancer Center Support Grant.
Molecular Mechanisms of Progression from Familial Platelet Disorder to Acute Myeloid Leukemia
Familial platelet disorder (FPD) is caused by inherited mutations in the transcription factor RUNX1 and confers an increased risk of acute myeloid leukemia and certain other blood cancers. Agarwal hypothesizes that inherited RUNX1 mutations cooperate with acquired somatic mutations to dysregulate downstream signaling pathways to drive malignant transformation. Her project will use CRISPR/Cas9 to identify the contributions of germline RUNX1 mutations and co-occurring somatic mutations in AML transformation. The project also will test the efficacy of small-molecule inhibitors in blocking RUNX1-mediated signaling and transformation.
Enhanced delivery of antisense oligonucleotides into cancer cells using low dose radiation to silence MGMT in a metastatic brain tumor model
One cause of chemotherapy resistance in brain tumors is the DNA-repair enzyme MGMT. Prakash and colleagues have found that antisense morpholino oligonucleotides can turn off the gene that encodes MGMT, thus potentially making tumors more vulnerable to chemo. The project will evaluate the best route to administer the antisense agent to optimize passage across the blood-brain barrier in an animal model. And it will evaluate whether silencing the MGMT gene can boost the effectiveness of the chemotherapy drug temozolomide in a human tumor grown in a rat brain.
Targeting Endoplasmic Reticulum stress to enhance the tumor immune microenvironment
Anand’s lab has found that one way cancer cells may limit their exposure to anti-cancer immune system activity is by turning down the expression of a specific microRNA, miR-494. His project will investigate how restoring miR-494 affects tumor growth and influences immune function in mouse tumor and cell culture models. And the project will evaluate the efficacy of a small molecule drug that works similar to the microRNA. The goal is to enable the development of combination therapies that can invigorate anti-tumor immune responses.
Skin cancer prevention in a high-risk population: proof of principal for a new proprietary skin cancer prevention agent*
Cassidy and Leachman are planning a cancer prevention clinical trial testing a DNA-repair enzyme developed by R. Stephen Lloyd, Ph.D., and Amanda McCullough, Ph.D. The idea is to enlist a patient population with a 1,000-fold increased risk for UV-induced skin cancers. These patients develop new non-melanoma skin cancers at rates sufficiently high that statistically-powerful clinical tests of efficacy could enroll as few as 30 participants. The funded project involves planning an investigational new drug application, producing the drug in quantities sufficient to complete pre-clinical testing, and working with patient advocacy groups and experts and the National Cancer Institute to establish a registry of potential clinical trial participants.
A Platform Technology for Highly Multiplexed Immunofluorescence and Immunohistochemistry
Using current techniques, it is impossible to simultaneously assess the interactions of the multitude of proteins involved in cancer development. The Gibbs Lab has collaboratively developed a cyclic protein immunostaining technology that may be capable of imaging hundreds of proteins in a single sample. Proof of concept data show that the technology permits cycles of staining without compromising tissue integrity. And the same labeled antibodies permit immunofluorescence, immunohistochemistry and superresolution microscopy. The project will generate a suite of tagged antibodies for cyclic immunostaining and use them to successfully image at least 15 proteins on a single sample resulting in preliminary data for competitive national grants.
Novel zebrafish platform to assess adverse reactions of anti-cancer compounds
When multiple drugs are combined they may cause unexpected and severe side effects. Nechiporuk and colleagues propose to use larval zebrafish to test combinations of anti-cancer compounds for their toxicity in various organs systems. (Genome organization and the genetic pathways responsible for organ development and function appear to be highly conserved between zebrafish and humans, and zebrafish larvae are transparent – permitting direct observation of organ function.) The project will compare the zebrafish results with known human toxicity profiles to assess the potential of the system.
MammoScreen: A Tool to Identify Breast Cancer Risk and Guide Screening Decisions
MammoScreen is a web-based app that helps women make informed decisions about breast cancer screening. The project will expand and update the app and conduct a pilot study of its impact with the OHSU internal medicine primary care clinic. The study will include interviews and surveys of clinicians and patients, and collection of breast cancer risk data, screening intention, utilization, and clinical follow-up data from MammoScreen and patient medical records. MammoScreen will be expanded to include new, age-specific information about benefits and harms of screening for women of all relevant age groups; additional risk questions; customized messages directing patients to follow-up care; an electronic database of collected risk data; and customized reporting functions for clinicians.
Pilot Study of a Progressive Exercise Program among Lung Cancer Patient-Partner Dyads*
Nearly half of people with lung cancer experience symptoms of depression. And significant fraction – up to 13 percent – develop a major depressive disorder. Importantly, depression affects lung cancer patient outcomes. Sullivan and colleagues (Kerri Winters-Stone, Ph.D., and Karen Lyons, Ph.D.) are studying the potential benefits of partnered exercise for people with lung cancer. Up to 15 lung cancer patients and their dyad-partners will participate in a 3-month, progressive exercise program including yoga elements. The goal is to assess the feasibility of the exercise intervention and track depression symptoms, quality of life, physical and mental functioning, partner support, cancer treatment adherence, and mortality. The findings will be used to support a future, larger trial of the intervention.
Development of a novel melanoma immunotherapy with intrinsic ability to mitigate immunosuppressive tumor microenvironment
Cancer immune therapies have delivered life-saving, long-lasting results – but only in a fraction of patients. Yantasee’s group has engineered nanoparticles to co-deliver drugs that kill cancer and activate tumor-specific immune cells. The project will study how the nanoparticles effect the immunosuppressive tumor micro-environment in a mouse melanoma model. Yantasee, with a team including Amanda Lund, Ph.D., will assess the response of tumors treated locally with the nanoconstruct and also the response of distant untreated tumors due to systemic immunity.