Nine Cancer Research Projects Funded in Fall 2024 RAP Cycle

Can you describe the focus of your project in a few sentences?

Engineered cell therapies, in which immune cells are rewired to specifically recognize and kill cancer cells through the expression of a chimeric antigen receptor (CAR), represent one of the most exciting new innovations in cancer treatment. CAR-T immune cells are the most studied engineered cell therapy, but their success in Acute Myeloid Leukemia (AML) has been limited. Two major reasons for this are: 1) AML is difficult to target and most AML cell markers are also expressed on healthy cells resulting in serious toxicity, and 2) patients with AML do not have healthy T immune cells to rewire. Our goal with this project is to overcome both challenges by engineering CARS targeted to a novel target antigen (CD70) into a novel immune (natural killer) cell platform. Natural Killer cells have specific features that may make them better suited for killing AML. A key limitation with translational CAR-NK cell therapies however is the persistence of their anti-tumor response. We thus propose using a cutting-edge engineering strategy that simultaneously knocks down key NK inhibitory signals while introducing a CAR. We believe a best-in-class anti-CD70 CAR-NK cell rewired to override intrinsic inhibitory signals holds great promise as an off-the-shelf therapy for AML.

What motivated you to pursue this particular project?

Acute Myeloid Leukemia is a devastating disease in the relapsed and refractory setting with high mortality and treatment associated toxicity in both children and adults. Novel therapy options are urgently needed to improve patient outcomes, and our hope is to move the needle on innovative therapies through our proposed project.

Can you describe the focus of your project in a few sentences?

High-intensity focused ultrasound (HIFU) — a minimally-invasive, focal therapeutic approach — can benefit men with small-volume, unilateral, low- to intermediate-risk prostate cancer, yet early identification of residual/recurrent disease remains a major unmet need. Dual-agent pyruvate and urea hyperpolarized (HP) 13C molecular metabolic MRI uniquely characterizes both the aberrant metabolic hyperactivity and tissue blood flow disruptions in aggressive prostate cancers. This new approach provides important biomedical information unavailable through conventional imaging modalities. Our study aims to investigate the novel HP "viability" imaging biomarker (metabolism-tissue perfusion product) to optimize post-interventional monitoring, utilizing the 5-fold sensitivity provided by latest technical advancements including a cutting-edge 7T hyperpolarizer, fast MR pulse sequences, new sterile dual-agent pharmaceutical production methods and specialized analytics.

What motivated you to pursue this particular research?

Despite the promises of HIFU to achieve long-term prostate cancer control in select men while minimizing the morbidities associated with conventional surgery and radiation, its success is critically hampered by a lack of reliable imaging or serum biomarkers to accurately diagnose 30-40% post-HIFU recurrence. This PICT pilot team science combines the bright minds of UCSF Radiology, Genitourinary Oncology, and Urology to tackle this unmet clinical challenge by leveraging HP 13C dual-agent MRI that offers unique simultaneous real-time visualization of hypermetabolism and tissue hyperpermeability in recurrent prostate tumors for improved HIFU treatment assessment and identification of early failures.

Can you describe the focus of your project in a few sentences?

We hypothesize that a novel PET imaging targeting fibroblast activation protein (FAP) will provide significant benefits for addressing clinical challenges in breast imaging, particularly for invasive lobular cancer (ILC). We will test this hypothesis using dedicated breast PET (dbPET), a specialized PET system designed for breast imaging. By combining this high-resolution modality with a FAP-targeted radiotracer (FAP-dbPET), we aim to evaluate its ability to accurately detect invasive breast cancer and determine tumor extent and margins.

What motivated you to pursue this particular research?

There is a clear clinical need to improve breast imaging methods for invasive lobular carcinoma (ILC). We believe that FAP-dbPET could represent a significant advancement in this area, addressing this critical need. The primary goal of our pilot study is to assess the diagnostic capability of FAP-dbPET in effectively imaging primary breast cancer, including ILC. The data collected from this pilot study will be instrumental in designing a larger study utilizing FAP-dbPET.

Can you describe the focus of your project in a few sentences? 

We are interested in surface proteins expressed by cancer cells that can be utilized for cancer diagnostics and therapeutics. A conformation specific antibody targeting a tumor-specific epitope of CD46 was previously discovered by Dr. Bin Liu. In collaboration with Dr. Rob Flavell, we have shown that this antibody recognizes CD46 in pre-clinical prostate cancer models, which has allowed the team to move the research into a phase 1 clinical trial that is currently ongoing. In the current proposal, we are studying whether CD46 is expressed in different stages of bladder cancer, including cancer cells resistant to the current standard of care therapies. In addition, we will investigate whether this CD46-targeting antibody can also be used to detect bladder cancer in preclinical cell line and patient-derived xenograft models, with the goal of translating these studies into humans.

What motivated you to pursue this particular project?

We are hoping that this research will allow us to better diagnose and stage patients with bladder cancer, a disease in which there is no specific PET imaging tracer available. We are also hoping that we can translate this research into new therapies such as using antibody drug conjugates and radioimmunotherapies, to treat bladder cancer, particularly ones that have developed resistance to the current standard of care therapies.

Can you describe the focus of your project in a few sentences? 

Leukemia is a cancer of the developing blood cells which can occur at all ages affecting both pediatric and adult patients. Ikaros is a DNA-binding transcription factor that is an important tumor suppressor in acute lymphoblastic leukemia of the B-cell lineage (B-ALL). Ikaros mainly acts as a transcriptional repressor, through recruiting different chromatin remodeling complexes to the DNA. However, it is not known which proteins are required for Ikaros-mediated tumor suppressor function in B-ALL, and this project aims to investigate this through use of small molecule inhibitors and CRISPRi-screen.

What motivated you to pursue this particular project?

While outcome for patients with leukemia has greatly improved in the last decade, relapse is still a significant clinical challenge, with limited effective treatment options and high mortality. B-ALL can be divided into subtypes based on genetic lesions, and recurrent mutations in IKZF1, the gene encoding Ikaros, correlate with relapse and poor outcome. I am motivated by the vision that increased understanding of the underlying biology may illuminate cancer cell vulnerabilities and enable development of targeted therapies for personalized medicine. Chromatin remodeling complexes are targetable by small molecule inhibitors, and understanding the basic molecular mechanisms that are deregulated in IKZF1-mutant B-ALL may lead to future rational therapeutic targeting for patients with IKZF1-mutant B-ALL.

Can you describe the focus of your project in a few sentences? 

Breast cancer is one of the most common cancers in the U.S., and early detection and risk assessment are crucial for improving patient outcomes. Current imaging techniques face limitations in accurately assessing the risk associated with breast tumors. In this project, we propose developing a novel quantitative metabolic imaging protocol using hyperpolarized [1-13C]pyruvate MRI and a deep-learning based multiparametric prediction model to enhance risk stratification of breast tumors. By integrating advanced MRI acquisition techniques with deep-learning based analysis, we aim to provide more accurate and non-invasive assessments of tumor metabolism to support better clinical decision-making and patient management.

What motivated you to pursue this particular research?

I have spent four years at UCSF developing hyperpolarized 13C MRI technologies to monitor kidney diseases. During this time, I expanded my technical expertise beyond HP 13C MRI to include quantitative MRI, while also gaining knowledge in renal oncology. With this project, I aim to bridge my experience in HP 13C MRI and quantitative MRI and leverage my background in renal imaging to build collaborations with breast cancer experts. Additionally, this work addresses a significant research gap at UCSF, where hyperpolarized 13C MRI has been extensively studied but remains underutilized in breast cancer applications. Success in this project will deepen my understanding of MRI physics, broaden my expertise in molecular imaging, and provide valuable insights into clinical breast cancer research. I look forward to incorporating these perspectives into my future work.

Can you describe the focus of your project in a few sentences? 

In the Roose lab and Roose Organoid D2B unit we generate and utilize patient-derived organoids (PDO) with the broad goals of understanding “cancer cell fitness” as well as human and patient-specific features of specific cancer types and cancer metastasis. We developed an exciting spectral flow proteomics platform that allows for cell biological analysis of our biobanked PDO. In this RAP project, we will assess the effects of KRas-inhibitors on pancreatic ductal adenocarcinoma (PDAC) with the combined use of PDO and spectral flow.

What motivated you to pursue this particular project?

There has been a renaissance in the field of Ras inhibition and cancer therapy with various new Ras inhibitors in clinical trials. Unfortunately, reports of resistance to these therapies are also emerging. With our RAP-supported research, we aim to obtain novel insights into such resistance by analyzing the cellular- and cell metabolic- characteristics of inhibitor resistant cells in PDAC PDO. Critically, the spectral flow will provide insights that cannot be obtained by sequencing methods.

Can you describe the focus of your project in a few sentences?

Gynecologic cancer patients undergoing treatment often face challenges including severe fatigue, muscle loss, and reduced physical activity, which impact their quality of life. Exercise has been shown to help cancer patients feel stronger and more energized, but most research has focused on those who have finished treatment. Patients currently receiving treatment—including gynecologic cancers—have been largely overlooked. The EMPOWER study (Exercise and Movement to Promote Our patients With gynecologic cancer to Enhance Resiliency) aims to address this. We will use an innovative approach combining wearable technology, a digital platform that utilizes virtual digital physical therapists that personalize exercise plans, and an online support group led by a certified health coach, to make exercise accessible and tailored for patients in treatment.

What motivated you to pursue this particular research?

The program addresses common barriers like physical symptoms, stress, need for social support, and hopes to be able to bring this to underserved areas that may have limited access to specialized care. By harnessing technology and community support, EMPOWER seeks to improve the physical and emotional well-being of patients during treatment. If successful, this program could pave the way for accessible, scalable solutions that enhance quality of life for gynecologic cancer patients nationwide.

Can you describe the focus of your project in a few sentences? 

We are excited to embark on this team science project, which establishes a multidisciplinary collaboration between Co-PIs Dr. Kord Kober (School of Nursing), Dr. Nam Woo Cho (Radiation Oncology), and Co-I Dr. Sue Yom (Radiation Oncology). The project aims to understand cancer-related fatigue, a crippling and pervasive symptom for our patients treated with chemotherapy and radiotherapy that compromises treatment tolerability and quality of life. Adding to this challenge is that the molecular mechanisms responsible for cancer-related fatigue are quite poorly understood. In this project, we will deeply profile immune cells in patients undergoing chemotherapy and radiotherapy by quantifying the changes in protein and RNA. Importantly, we aim to distinguish changes caused by the cancer itself, or by therapy, which will allow us to identify precise targets to predict and counter cancer-related fatigue.

What motivated you to pursue this particular research?

We see first-hand how cancer-related fatigue affects nearly all patients we treat in the clinic. What is even more frustrating is the fact that our armamentarium is limited due to our lack of insight into the mechanisms driving this symptom. Our expertise with latest generation immune-profiling techniques opens an opportunity to reveal cells and molecular pathways that cause cancer-related fatigue, and the lessons learned can inform new strategies to improve the lives of cancer patients.