Two projects underscoring basic/clinical partnerships in translational research have been awarded the two-year, $100,000 grants from the University of Arizona Cancer Center. Congratulations to Linda Garland, MD, and Heidi Hamann, PhD, and Daruka Mahadevan, MD, PhD, and Nathan Ellis, PhD. This award is supported by the NCI Cancer Center Support Grant.
Clinical PI: Linda Garland, MD
Basic Science PI: Heidi Hamann, PhD
Project Title: “An innovative approach to reduce lung cancer stigma”
Background
Experiences of stigma (perception and internalization of negative appraisal and devaluation from others} are pervasive for lung cancer patients. Previous work (including ours) has shown associations between lung cancer stigma and detriments in clinically relevant outcomes: depression, lower quality of life, and reduced engagement in cancer care. A promising target for patient-focused intervention is to reduce the self-blame, guilt, and inhibited disclosure associated with lung cancer stigma. Acceptance and Commitment Therapy (ACT), a cognitive-behavioral treatment that promotes psychological flexibility through acceptance and valued direction, provides coping tools to target these aspects and alleviate lung cancer stigma.
Specific Aims
This proposal will examine the feasibility, acceptability, and preliminary efficacy of an innovative, ACT-based intervention to reduce stigma among lung cancer patients.
- Aim 1: Using mixed methods, we will develop and refine an ACT intervention treatment manual for patients with lung cancer (ACT-LC) based on iterative patient and clinical expert feedback.
- Aim 2: In a pilot randomized controlled trial (RCT) of lung cancer patients, we will examine the feasibility, acceptability, and preliminary efficacy of an ACT-LC intervention.
Research Design
For Aim 1, we will develop and refine an alpha version of an ACT-LC treatment manual by eliciting and integrating feedback from professional colleagues and lung cancer advocates. Then, we will recruit 1O lung cancer patients who report high levels of stigma (based on our validated measurement tool) from Dr. Garland's thoracic oncology clinic. Two trained therapists will deliver the alpha version of the ACT-LC treatment, integrating feedback into a beta version of the treatment. For Aim 2, we will use this beta version and conduct a pilot RCT (total N=40; 1:1 distribution of treatment v. usual care) assessing feasibility, acceptability, and preliminary efficacy (reductions in patient-reported stigma and other psychosocial outcome) of the intervention for highly stigmatized lung cancer patients.
Cancer Relevance
Demonstrating feasibility, acceptability, and initial efficacy of the intervention will allow us to further study (in a large Ren the intervention's effects on longer-term health and psychosocial outcomes of lung cancer patients. The National Cancer Institute (NCI) and the American Lung Association (ALA) have mechanisms to support such trials. In contrast to the wide array of services available for other patient groups (e.g., breast, prostate), there are few psychosocial support services to meet the unique needs of lung cancer patients. This intervention has potential for rapid implementation into clinical supportive care services at the UACC and other cancer centers.
Dr. Garland is associate professor of clinical medicine in the UA Division of Hematology and Oncology and director of the Clinical Lung Cancer Program and an investigator in the Cancer Prevention and Control Program at the UA Cancer Center.
Dr. Hamann is an associate professor of family and community medicine in the UA College of Medicine – Tucson and psychology in the UA College of Science and a member of the UA Cancer Center.
Clinical PI: Daruka Mahadevan, MD, PhD
Basic Science PI: Nathan Ellis, PhD
Project Title: “Targeted therapies for homologous recombination-proficient head & neck cancer”
Background
Homologous recombination (HR) is a high-fidelity DNA double strand break repair (DSBR) process and a mechanism that stabilizes replication forks during genotoxic stress. Human tumors with deficient HR, such as when BRCA mutations are present, exhibit increased sensitivity to platinum-based agents and to PARP inhibitors. On the other hand, up-regulation of HR acts as a compensatory DNA repair mechanism that drives tumor cell radio- and chemo-resistance. Consequently, identification of molecular targets that when inhibited down-regulate the HR pathway could potentially sensitize resistant tumor cells to chemotherapy (e.g., platinum) and to irradiation. The RAD51 recombinase is the key enzyme in HR-directed DSBR, and it constitutes an attractive target. Our group originally identified amuvatinib as a receptor tyrosine kinase inhibitor. Subsequent research has shown that amuvatinib binds the ATP binding pocket of RAD51 and inhibits HR. We propose to inhibit the HR pathway using amuvatinib to sensitize HR-proficient cancer cells to chemo-radiation.
Hypothesis
Proficient HR and DSBR pathways enforce tumor cell resistance to standard therapeutic regimens in head and neck squamous cell cancer (HNSCC). Amuvatinib binds to RAD51 directly and inhibits it. Treatment of HR-proficient cancers with amuvatinib will sensitize them to platinum-based DNA damaging agents and to radiation.
Specific Aims
- Aim 1: Determine the biochemical properties and effects of amuvatinib binding on RAD51.
- Aim 2: Determine the efficacy of sensitization of HR-proficient HNSCC cell lines by amuvatinib in tissue culture and orthotopic mouse models.
Research Design
In Aim 1, we will quantitate binding of amuvatinib to RAD51 using X-ray crystallography and surface plasmon resonance. We will generate and test mutant RAD51 proteins that disrupt binding to confirm the involvement of key amino acids in binding. We will characterize in vitro the effects of binding of amuvatinib on standard biochemical functions of RAD51, such as single-stranded DNA binding, ATP hydrolysis, and strand invasion assays. In Aim 2, we will compare the efficacy of amuvatinib on HNSCC cell lines that are HR-proficient and HR-deficient. We will characterize the effects of amuvatinib treatment + DNA damage on HR function using RAD51 immunofluorescence, -H2AX flow cytometry, and DSB assays. We will test sensitization of HNSCC cell lines to platinum-based agents and to irradiation in colony survival, apoptosis, and MTT assays. We will test the effects of amuvatinib on tumor progression using orthotopic mouse models.
Cancer Relevance
HR maintains genomic stability, promotes cell survival, and mediates therapy resistance. Blocking HR pathway function by therapeutic targeting of RAD51 will sensitize HR-proficient cancer cells to chemo- and radio-therapy. Because amuvatinib has completed Phase I and II trials, this research will quickly lead to new trials of combinatorial treatments in combination with companion diagnostics for tumor HR-proficiency.
Dr. Mahadevan is a professor of medicine in the UA Division of Hematology and Oncology and co-program leader for the Therapeutic Development Program and director of the Phase I Program at the UA Cancer Center.
Dr. Ellis is an associate professor of cellular and molecular medicine and cancer biology and genetics in the UA Graduate Interdisciplinary Programs and scientific director of the Cancer Biology Research Program at the UA Cancer Center.