Research that’s Practice Changing Paradigm Shifting & Policy Creating
November 30, 2023
The challenge to accomplish “practice-changing, paradigm-shifting, policy-creating” research is one that scientists and clinicians at Vanderbilt-Ingram Cancer Center have often heard from Jennifer Pietenpol, PhD.
Those words are like a mantra for Pietenpol, Executive Vice President for Research, chief scientific and strategy officer for Vanderbilt University Medical Center (VUMC) and holder of the Brock Family Directorship in Career Development. She challenged research teams to focus on these basic goals during her tenure as director of Vanderbilt-Ingram from 2007 to 2022 and continues to do so in her current leadership role.
A new initiative, the P3 Catalyst Awards, has been launched to fund investigators who aim for these big impact goals — research that changes how cancer care is practiced, and research that shifts the understanding of cancer mechanisms and creates public policies to lessen the burden of cancer on people’s lives.
Six projects were chosen in 2023 for the first grant awards through this initiative.
Clonal hematopoiesis and ovarian cancer survivorship
Alexander Bick, MD, PhD, recipient
Chic Awearness, donor
This research project aims to find out whether patients with ovarian cancer have a higher risk of developing a blood disorder called clonal hematopoiesis or blood cancers. The research team will look at the medical records of patients with ovarian cancer treated at VUMC from 2010 to 2020 and analyze their blood samples.
The researchers are particularly interested in analyzing patients who are taking PARP inhibitors, a new class of therapy for ovarian cancer. If patients taking PARP inhibitors have less clonal hematopoiesis, it may be repurposed as a treatment for blood cancer. Overall, the goal is to learn more about the relationship between ovarian cancer and these blood disorders, which could help doctors detect and treat them earlier, ultimately improving patients’ quality of life and long-term survival.
Repurposing HER2 inhibitors in prostate cancer
Paula Hurley, PhD, recipient
Clip In 4 the Cure, donor
Metastatic prostate cancer is currently an incurable and lethal disease. Testosterone activation of the androgen receptor (AR) pathway is critical for prostate cancer, and thus, a large class of therapies for prostate cancer has focused on inhibiting the AR pathway through testosterone and AR suppression.
Most men with metastatic prostate cancer initially benefit from AR-targeted therapies; however, their cancer ultimately recurs despite continued therapy. Recurrence happens through two broad mechanisms: The cancer gains the ability to activate AR in a manner that escapes AR-targeted therapies, or the cancer no longer needs AR for survival and growth. Both mechanisms of recurrence highlight the paradigm-shifting need for non-AR targeted therapies for metastatic prostate cancer.
The research team’s preliminary data support a mode in which noncancer cells called cancer-associated fibroblasts (CAF) within the tumor drive prostate cancer cells to no longer need AR for survival through the activation of HER2, a current therapeutic target for HER2-amplified breast cancers. Hurley and her research team aim to, first, demonstrate CAF-mediated activation of HER2 in prostate cancer cells as a mechanism of resistance to AR pathway inhibitors and, second, validate HER2 as a novel therapeutic target for metastatic prostate cancer.
Rigosertib and pembrolizumab in anti-PD-1 refractory melanoma
Doug Johnson, MD, MSCI, recipient
Clip In 4 the Cure, donor
The use of immune therapy has changed metastatic melanoma from universally fatal to a disease where approximately half of patients experience long-term survival. However, the other half of patients experience resistance with tumors that evade the immune system. With work done in the Ann Richmond Lab at Vanderbilt University, researchers discovered a promising strategy to reawaken the immune system for resistant melanomas.
Specifically, a drug called rigosertib, when given in combination with the commonly used immunotherapy treatment pembrolizumab, causes improved immune attacking of resistant melanomas in mouse models. The researchers have designed a clinical trial combining rigosertib and pembrolizumab in patients who have failed available therapies.
Predicting therapeutic outcomes in triple-negative breast cancer
Justin Balko, PharmD, PhD, recipient
Richard S. Reynolds Foundation Breast Cancer Fund, donor
Many newly diagnosed breast cancer patients get a combination of different types of therapy before they undergo surgery. Currently, triple-negative breast cancer is treated with both chemotherapy and immunotherapy. This combination helps more patients but also causes more toxicity.
There are three groups of patients in this setting — ones that need all the drugs to get the best response, ones that need only the chemotherapy, and ones that won’t respond to any of the therapies. Patients who don’t respond to any of the therapies are best for new clinical trials, but currently clinicians cannot differentiate between the three groups of patients.
The researchers will leverage a huge resource of blood samples from a national clinical trial to identify minimally invasive markers to tell these patients apart.
Mixed reality visual aid to guide head and neck cancer surgeons
Michael Topf, MD, recipient
Swim Across America, donor
To address an unmet need, Topf and his team aim to create an intraoperative, mixed-reality hologram to assist head and neck surgeons. The technology will be built upon an existing protocol they have developed for 3D scanning of resected tumors. The overall goal is to improve real-time communications between surgeons and pathologists.
Currently, these communications are limited to telephone conversations without visual aids between the surgeon in the operating room and the pathologist in the lab. Surgeons rely on pathologists and intraoperative frozen section analysis to determine if there is cancer remaining in the patient, or a positive surgical margin, after removal of a tumor. The pathologist analyzes the frozen tumor specimen, then tells the surgeon the findings.
The team plans to design a system that will create a hologram of the virtual 3D specimen model that will project onto and align with the surgical resection site. The overarching goal is to improve the accuracy of relocating and re-resecting positive surgical margins. This new technological protocol could also be used for solid tumors with other cancers and be practice-changing for surgical oncology.
A diagnostic marker of anaplastic thyroid carcinoma
Vivian Weiss, MD, PhD, and Ethan Lee, MD, PhD, recipients
Justin and Valere Potter Foundation, donor
Anaplastic thyroid cancer is highly lethal with only a four-month median survival. Weiss, Lee and their research team aim to develop new screening tools for the early detection of anaplastic thyroid carcinoma.
There is currently no way to predict which patients will develop this type of deadly thyroid cancer at the time of biopsy or surgery. While the majority of patients are cured of their thyroid cancer following initial treatment, approximately 10% to 20% will have disease recurrence, metastatic disease or transform to anaplastic thyroid cancer. With thyroid cancer expected to be the fourth leading cancer diagnosis in the U.S. by 2030, surpassing colorectal cancer, improved identification and personalized treatments for patients must be a priority.
Utilizing a large cohort of about 250 Vanderbilt patients, the research team has identified keratin 5 as a potential marker of anaplastic thyroid carcinoma. Their next steps are validating keratin 5 as a screening tool and discovering how keratin expression is controlled in anaplastic thyroid carcinoma.