Since 2009, Swim Across America has contributed more than $5.3 million for cancer research at Fred Hutchinson Cancer Center. Funds raised by the event and by the motivated swimmers who participate enable early-career investigators to pursue groundbreaking research that can improve care for patients in Seattle and beyond. Investigators who received funding in previous years continue to build on research made possible by Swim Across America to advance understanding of breast cancer, lymphoma, pancreatic cancer, and sarcoma. We are delighted to provide this year’s update on the projects you’ve supported below. Don’t forget to register for this year’s Swim Across America – Seattle!

Meghan R. Flanagan, MD, MPH | Breast Cancer 

Physician and affiliate investigator, Fred Hutch; Assistant professor of Surgery, UW Medicine 

Project: Association of HSD3B1 (1245C) genotype with recurrence among post-menopausal women with estrogen receptor-positive, HER2- negative breast cancer 

Background: Anti-estrogen endocrine therapy reduces the risk of recurrence and improves breast cancer mortality among individuals with hormone-receptor positive breast cancer. However, approximately one-quarter of patients are inherently resistant or develop resistance to endocrine therapy. Ultimately, this research may allow us to identify people with innate endocrine resistance and develop novel therapeutics and treatment strategies. 

Progress statement 2022: Swim Across America’s initial support helped our team evaluate whether there is an association between a common single nucleotide variation in a gene called HSD3B1 (which is involved in hormone biosynthesis) and breast cancer outcomes. Using an extensive collection of clinical and pathologic data about patients and their tumors, we demonstrated that patients with two copies of the variant in the HSD3B1 gene had a five-fold increased risk of developing metastatic breast cancer, compared to people who did not have this variant. 

In July 2022, we published findings from Swim Across America-supported research in the Annals of Surgical Oncology. Based on these results, our team received funding to study whether inheriting two copies of the variant HSD3B1 gene — which occurs in 10% to 15% of patients with estrogen receptor-positive, post-menopausal breast cancer — decreases the effectiveness of anti-estrogen medications, which are used universally in this population. Our results could indicate the need for alternative treatment strategies for these patients. 

2023 update: 33 of 60 patients have completed the study, and frozen tissue from 25 patients has been analyzed for estrogen and androgen concentrations. Although only two patients had two copies of the variant HSD3B1 gene, and we do not have enough information to make conclusions about the variant versus wild-type gene, it is likely that our analysis will be the most comprehensive steroid profiling of normal and tumor breast tissue. We are also in the process of finalizing data for our primary study outcomes and anticipate this will be completed in the late spring. 

Sita Kugel, PhD | Pancreatic Cancer 

Assistant professor, Fred Hutch 

Project: Exploring novel functions of HMGA2 in pancreatic cancer 

Background: Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal disease with an overall five-year survival rate of 12%. Recent work has led to the discovery that PDA can be subdivided into two principal subtypes based on transcriptional signatures: classical and basal. The basal subtype is more aggressive and leads to the worst overall survival. Our laboratory has been focused on understanding the mechanisms that drive each subtype with the aim of identifying therapeutic vulnerabilities that may be exploited in the clinic. 

Progress statement 2022: Within an already challenging malignancy, certain transcriptional subtypes of pancreatic ductal adenocarcinoma are especially lethal. Funding from Swim Across America is helping us understand what defines each subtype, as well as their susceptibilities and mechanisms of resistance, to help to identify potential new treatment options for this devastating disease. Our team has recreated the classical and basal subtypes in the lab and managed to explore the differences between the two, including how they acquire resistance to first-line therapies. Our work will lay the groundwork for more targeted treatments for PDAs that can also account for their respective escape mechanisms, thereby improving outcomes. 

2023 update: Some of our recent work showed that basal pancreatic tumors are sensitive to cyclin-dependent kinase (CDK) inhibitors. Our team is trialing these CDK inhibitors in patients who are also receiving standard-of-care treatment, while also looking at whether a different treatment combination affects one tumor subtype more than the other. 

Simultaneously, we are using pancreatic tumor tissue taken from patients and grown in mice to test new treatment strategies in an environment similar to the human body. 

Jonathan Sham, MD, MBEE | Pancreatic Cancer 

Surgical oncologist and assistant professor, Fred Hutch and UW Medicine 

Project: Novel drug-eluting biopolymer to reduce pancreatic fistula and improve outcomes after pancreatic surgery 

Background: Pancreatectomy, or removal of the pancreas, is the mainstay of any potentially curative treatment regimen for pancreatic cancer. Despite an overall improvement in the safety of pancreatic surgery over the past several decades, the morbidity of pancreatectomy remains exceedingly high. The most significant complication after pancreatic surgery is postoperative pancreatic fistula (POPF), which occurs in up to 50% of cases. The use of a biopolymer, poly(N-isopropylacrylamide) (PNIPAM), is an innovative approach to prevent leakage of pancreatic juice from the cut surface of the gland, while drug-eluting microspheres aims to simultaneously reduce baseline pancreatic fluid secretion. This novel dual-action approach will be tested in a validated rat model of POPF with the goal of rapid clinical translation and patient benefit. 

Progress statement 2022: Swim Across America is advancing our work to improve outcomes after pancreatic surgery. Your support is enabling a trailblazing collaboration between surgeons and bioengineers to develop novel ways to stop leaks after pancreas surgery and help patients live healthier and longer lives. We have also expanded our team and published our groundbreaking research, including our development of a preclinical model for studying POPF. We continue to move this work closer to helping patients with pancreatic cancer. 

2023 update: We are continuing to optimize biopolymer performance and handling characteristics for use during surgery. We are also including a chemical approach that clams use to adhere to underwater rocks in order to maximize adhesion on wet surfaces during surgery. 

Jordan Gauthier, MD, MsC | Lymphoma 

Physician and assistant professor, Fred Hutch and UW Medicine 

Project: Factors associated with failure of CD19 CAR T cells in diffuse large B-cell lymphoma 

Background: We are investigating two factors — T-cell dysfunction during manufacturing and the suppressive tumor microenvironment — that may play a critical role in the failure of CD19-targeting chimeric antigen receptor (CAR) T-cell therapy for people with diffuse large B-cell lymphoma (DLBCL). We are also working to identify potential targets to improve outcomes of CAR T-cell therapy for patients with DLBCL. 

Progress statement 2022: The Swim Across America grant allowed us to explore two parallel questions. First, to understand whether exhausted T cells are associated with treatment failure after CAR T-cell therapy for patients with DLBCL, we analyzed blood samples from 34 patients treated on a clinical trial. While we did not confirm an association between exhausted T cells and treatment failure, we found that a higher proportion of terminally differentiated T cells may have an adverse impact on the outcomes of CAR T-cell therapy. Second, to determine if an exhausted gene signature in T cells from lymphoma tumors is associated with treatment failure, we analyzed pre-treatment tumor biopsies from 17 patients receiving CAR T-cell therapy. In patients who had a complete response to CAR T-cell therapy, we found that T-cell-associated genes were overexpressed compared to patients not in complete response after treatment. Our results suggest that tumors more susceptible to T-cell infiltration might respond better to CAR T-cell therapy. 

Funds from Swim Across America also supported the development of two cutting-edge approaches, CITE-seq and CODEX, that allow us to study proteins and DNA from single cells and take 3D photographs of biopsies before and after therapy. These tools will help us better understand why CAR T-cell therapy does not work in some patients. Identifying why treatment fails at a single-cell level will have a dramatic impact on how we design the next generation of CAR T-cell therapies. 

2023 update: Using tools we developed with the support of Swim Across America, we are now able to specifically study how CAR T cells “talk” to other cells inside lymphoma tumors. We are also now using CITE-seq to analyze 20 tumor biopsy samples from patients undergoing CAR T-cell therapy in clinical trials. We are looking at associations between specific immune cell populations and outcomes, such as anti-cancer effects and toxicity. 

John K. Lee, MD, PhD | Sarcoma 

Previously physician and assistant professor, Fred Hutch and UW Medicine; currently at UCLA 

Project: Development of STEAP1 chimeric antigen receptor T-cell therapy for Ewing sarcoma 

Background: Approximately 200 adolescents and young adults in the U.S. are diagnosed each year with Ewing sarcoma, a cancer of the soft tissue and bone. When Ewing sarcoma spreads, patients face a very grim prognosis, as no available treatments eradicate the disease. If successful, our studies will help lay the groundwork for the development and clinical translation of a first-in-field CAR T-cell immunotherapy for Ewing sarcoma that targets the protein STEAP1. 

Progress statement 2022: Swim Across America funding helped us evaluate whether a novel CAR T-cell therapy targeting the protein STEAP1 could be an effective strategy to treat patients with Ewing sarcoma. Our results indicate that human Ewing sarcoma tumor models commonly express STEAP1 and are susceptible to killing by STEAP1 CAR T cells. In related studies, we have also determined that STEAP1 CAR T-cell therapy appears safe in a novel mouse model that we engineered to express human STEAP1. We have seen highly promising activity in multiple preclinical models of Ewing sarcoma, and we licensed the technology to a company for clinical development. 

2023 update: The Swim Across America grant enabled studies, now complete, confirming the anti-cancer activity of STEAP1 CAR T-cell therapy in preclinical models of Ewing sarcoma. A clinical trial in humans at Fred Hutch and Seattle Children’s Hospital is now being planned. 

To date, Swim Across America has contributed close to $4.2 million for clinical research at Seattle Cancer Care Alliance and Fred Hutch. Starting in 2019, funds raised from the SAA-Seattle have gone to support breakthrough research by young investigators. In 2021, six grants were awarded to researchers focused on: lymphoma, sarcoma, breast, pancreatic, and urological cancer research. Below, the grant recipients share progress statements on their research over the last year.

Dr. Meghan Flanagan
Research focus: Breast cancer
Project title: Association of HSD3B1 (1245C) genotype with recurrence among post-menopausal women with estrogen receptor- positive, HER2- negative breast cancer
Background: Endocrine (antiestrogen) therapy reduces the risk of recurrence and improves mortality among women with hormone-receptor positive breast cancer. However, approximately one-quarter of women are inherently resistant or develop resistance to endocrine therapy. Ultimately, this research may allow us to identify women with innate endocrine resistance and develop novel therapeutics and treatment strategies.
Progress Statement: The SAA funds were used to evaluate whether an association exists between a mutation in a gene (HSD3B1, involved in hormone biosynthesis) and breast cancer outcomes. Using extensively collected clinical and pathologic data about patient demographics, tumor and treatment data and recurrence rates, we were able to show that women with two mutations in the HSD3B1 gene had higher rates of distant metastatic recurrence compared to those women who did not have this mutation. Future studies will be forthcoming to determine how this mutation may decrease the effectiveness of anti-estrogen medications that are used universally in post-menopausal ER+ breast cancer. This mutation is found in up to 15 percent of ER+ post-menopausal breast cancer patients, and if shown to decrease the effectiveness of anti-estrogen medications, there would be potential indications for alternative treatment strategies in these patients.

Dr. Sita Kugel
Research focus: Pancreatic Cancer
Project title: Exploring novel functions of HMGA2 in pancreatic cancer
Background: Pancreatic Ductal Adenocarcinoma (PDA) is an extremely lethal disease with a 5-year survival rate of less than 10%. Recent work has led to the discovery that PDA can be subdivided into two principal subtypes based on transcriptional signatures: classical and quasi-mesenchymal (QM). The QM PDA subtype is more aggressive and has the worst overall survival. Our laboratory has been focused on understanding of the mechanisms that drive each subtype in hopes of identifying therapeutic vulnerabilities that may be exploited in the clinic.
Progress Statement: Within an already challenging malignancy, there are transcriptional subtypes of pancreatic ductal adenocarcinoma that are especially lethal. Understanding what defines each subtype, as well as their susceptibilities and mechanisms of resistance, will help to identify new targeted therapies or combination therapies and lead to more treatment options for this devastating disease.

Dr. Jonathan Sham
Research focus: Pancreatic Cancer
Project title: Novel Drug- eluting Biopolymer to Reduce Pancreatic Fistula and Improve Outcomes After Pancreatic Surgery
Background: Pancreatectomy is the mainstay of any potentially curative treatment regimen for pancreatic cancer. Despite an overall improvement in the safety of pancreatic surgery over the past several decades, the morbidity of pancreatectomy remains exceedingly high. The most significant complication after pancreatic surgery is postoperative pancreatic fistula (POPF), which occurs in up to 60% of cases. The use of a biopolymer, poly(Nisopropylacrylamide) (PNIPAM), is an innovative method to prevent leakage of pancreatic juice from the cut surface of the gland, while the suspended octreotide- eluting microspheres will simultaneously reduce baseline pancreatic fluid secretion. This novel dual-action approach will be tested in a validated rat model of POPF with the goal of rapid clinical translation and patient benefit.
Progress Statement: Swim Across America is advancing our work to improve outcomes after pancreatic surgery. Their support is enabling a trailblazing collaboration between surgeons and bioengineers to develop novel ways to stop leaks after pancreas surgery and make patients live happier, healthier and longer lives. Polymer synthesis is moving forward, and two teams are working on creating and testing polymers with different characteristics for use in our animal experiments.

Dr. Jordan Gauthier
Research focus: CAR T-cell therapy
Project title: Factors associated with failure of CD19 CAR T cells in diffuse large B cell lymphoma
Background: We are investigating two factors potentially critical to failure of CD19 CAR T-cell therapy for DLBCL: a) T cell dysfunction, impeding the generation of functional CAR T cells during manufacturing; b) the suppressive tumor microenvironment (TME). Our studies will better characterize T cell dysfunction and the TME as core mechanisms of failure of CD19 CAR T cells and identify potential targets to improve outcomes of CAR T-cell therapy for DLBCL.
Progress Statement: The Swim Across America grant allowed us to explore the two following aims.
Aim 1: To determine whether exhausted T cells are associated with treatment failure after CAR T-cell therapy for diffuse large B-cell lymphoma (DLBCL). We analyzed blood samples from 34 DLBCL patients treated on a clinical trial of CAR T-cell therapy. While we did not confirm an association between exhausted T cells and treatment failure, we found that a higher proportion of terminally differentiated T cells may have an adverse impact on the outcomes of CAR T-cell therapy.
Aim 2: To determine if an exhausted gene signature in T cells from lymphoma tumors is associated with treatment failure, we analyzed pre-treatment tumor biopsies obtained from 17 patients receiving CAR T-cell therapy. In biopsies from patients in complete response after CAR T-cell therapy, we found that T cell-associated genes were overexpressed compared to patients not in complete response after treatment. This suggests that tumors more permissive to T cell infiltration might respond better to CAR T-cell therapy. So far, we have not confirmed that an exhausted gene signature is associated with treatment failure. The SAA grant has been used to design and optimize novel assays that will allow us to further address this aim in the future.

Dr. John Lee
Research focus: Sarcoma
Project title: Development of STEAP1 chimeric antigen receptor T-cell therapy for Ewing sarcoma
Background: Ewing sarcoma (ES) is a soft tissue/bone cancer with 200 newly diagnosed adolescents/young adults per year in the United States. Patients with metastatic dissemination face a very grim prognosis as available treatments are unable to eradicate the disease. New therapeutic approaches are needed. If successful, these studies will help lay the groundwork for the development and clinical translation of a first-in-field STEAP1 CAR T-cell immunotherapy for ES.
Progress Statement: We applied the Swim Across America grant to evaluate whether a novel chimeric antigen receptor (CAR) T cell therapy targeting the protein STEAP1 could be an effective strategy to treat Ewing sarcoma. Our results indicate that human Ewing sarcoma tumor models commonly express STEAP1 and are susceptible to killing by STEAP1 CAR T cells. In related studies, we have also determined that STEAP1 CAR T cell therapy appears safe in a novel mouse model that we engineered to express human STEAP1. Together, these findings provide the rational to translate STEAP1 CAR T cell therapy into clinical trials for Ewing sarcoma in the near future.

Dr. Adam Gadzinski
Research focus: Urological cancer
Project title: Interstate Telehealth to improve access to urological cancer care among rural patients.
Background: Timely access to urological cancer care is challenging for rural patients who often travel great distances to tertiary centers. This is particularly true for patients residing in the WWAMI (Washington, Wyoming, Alaska, Montana, Idaho) region. We hypothesize that Telehealth will provide similar patient satisfaction, reduced costs, and earlier time to treatment. We further hypothesize that implementation of the interstate Telehealth program will decrease referral to visit time and increase clinical efficiency. Lastly, we hypothesize that providing Telehealth appointments will increase the frequency of referrals from rural areas. We anticipate that implementation of our interstate Telehealth program will improve access to urological cancer care for rural and underserved patients throughout the WWAMI region.
Progress Statement: Our SAA grant has been used to support our telemedicine research efforts to assess the quality of telemedicine visits for cancer patients from rural areas and the Pacific Northwest states. We have demonstrated that telemedicine visits save cancer patients and their families a significant amount of time and money that would have been spent traveling to doctor appointments. We also found that patients are very satisfied with receiving cancer care remotely via telemedicine, especially during the COVID-19 pandemic.