RAP Impact Awardees: Spring & Fall 2019 (compiled: June 2024)
Rosemary Akhurst, PhD
Professor – HDF Comprehensive Cancer Ctr.
School of Medicine
Team Science Grant
Co-PIs: Alain Algazi, MD; Allan Balmain, PhD
Co-Investigators: Sarah Arron, MD, PhD; Luke Gilbert, PhD; Mi-Ok Kim, PhD; Matt Spitzer, PhD; Jim Wells, PhD
Interplay between immune checkpoint blockade, TGFβ-signaling and cancer initiating cells in squamous carcinomas: Mechanisms, Biomarkers and Novel Targets for Immunotherapy
Awarded $ 75K – Spring, 2019
Original Organizational Aims were to:1) Create a team of basic and clinical scientists with the purpose of translating data from studies on mouse models of cutaneous squamous cell carcinoma (cSCC) into developing new drugs in clinical oncology practice for SCC of the head and neck (HNSCC) and metastatic or unresectable cSCC. 2) Develop the structure and organization for a PPG proposal for submission to the NCI or NIADS on therapeutic targeting of SCCs.
Original Scientific Aims of Pilot were to: Translationally validate our preclinical murine cSCC findings of induction of intratumoral TGFβ/Smad3 signaling by α-PD-1 therapy in human HNSCC and cSCC, and to investigate whether a driver of cSCC stem cells found in mice, Leucine-rich G-Protein Coupled Receptor 6(LGR6), is expressed in human SCCs, and further induced in response to α-PD-1 therapy, making it a novel oncology drug target. In the longer term, the team planned to develop a multi-PI federal grant, to identify additional novel drug targets using CRISPR/Cas9 screens in mice in vivo and develop new drugs for clinical oncology for SCC.
How did the RAP grant allow for further funding and/or publications?
Stimulation of collaboration between clinicians and basic researchers directly resulted in the recent award* of a multi-PI RO-1 grant to Akhurst and Balmain (co-PIs) with co-investigators Algazi, Gilbert, and Spitzer, entitled “A network approach to interrogate cellular plasticity and drug resistance in cancer”. The RAP award also stimulated or supported the following publications; a) Dodagatta, Ma, et al. Cell Reports, 2021, from the Akhurst and Dean Sheppard labs1 reporting the testing and mechanistic investigation of a novel cancer drug for immunotherapy in the mouse cSCC model that is now in clinical trial; b) Rahim et al Cell, 20232, from the Spitzer and Algazi labs examined T cell responses to anti-PD-L1 cancer immunotherapy in human regional lymph nodes (LNs) and blood of human HNSCC patients using mass cytometry, single-cell genomics, and multiplexed ion beam imaging. The data identified important roles for LNs in anti-tumor immune responses in humans, and showed that in metastatic LNs, hallmarks of CD8+ T cell activation in response to therapy were impaired, causing immunosuppressive cellular niches, c) Taylor et al. Science, 2024, from the Balmain and Akhurst labs3 used gene expression network analysis to investigate expression networks or “metagenes” within cancer stem cell states and how these are rewired in response to therapeutic treatments; this work may point to transcriptional vulnerabilities that could be targeted for drug development.
*The proposal to the NCI was scored in the top 2 percentile and is highly likely to be funded from October 2024, but the award has not yet officially been made.
Publications:
1. Dodagatta-Marri E, Ma HY, Liang B, Li J, Meyer DS, Chen SY, Sun KH, Ren X, Zivak B, Rosenblum MD, et al. Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy. Cell Rep. 2021;36:109309. doi: 10.1016/j.celrep.2021.109309
2. Rahim MK, Okholm TLH, Jones KB, McCarthy EE, Liu CC, Yee JL, Tamaki SJ, Marquez DM, Tenvooren I, Wai K, et al. Dynamic CD8(+) T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. 2023;186:1127-1143.e1118. doi: 10.1016/j.cell.2023.02.021
3. Taylor MA, Kandyba E, Halliwill K, Delrosario R, Koroshkin M, Goodarzi H, Quigley D, Li YR, Wu D, Bollam S, et al. Stem-cell states converge in multistage cutaneous squamous cell carcinoma development. Science. 2024;384:eadf7453.
What was the type of follow-up funding since the initial RAP award?
Akhurst, Balmain and Gilbert received three years of funding from BMS Pharmaceuticals for a project entitled, “Identifying Immune-Oncology Resistance Mechanisms in KRAS mutant cancers”. $390, 000 p.a. Dec 2019-Dec 2023 (including a 12 month no-cost extension).
Akhurst, Balmain, Algazi, Gilbert, and Spitzer, are in the process of being awarded a 5-year R0-1 grant entitled, “A network approach to interrogate cellular plasticity and drug resistance in cancer”, Oct 1st 2024-Sept 30th 2029
What is the focus of your research today?
The RAP team is studying a critical problem in clinical oncology, namely the widespread development of highly heterogeneous, drug resistant tumor cell populations. Most tumors develop resistance to almost every type of therapy, including targeted-, radiation-, chemo- or immuno-therapy, ultimately resulting in cancer deaths. It is essential to develop novel methods to understand the processes that lead to drug resistance under the complex conditions found in vivo where stromal and immune elements interact intimately with malignant cells.
We are studying squamous cell carcinomas (SCCs) in mouse, as representative of one of the most common human solid tumor types (SCCs) arising across a range of tissues including the head and neck, lung, esophagus, bladder, and skin. Together, these tumors make a major contribution to the human cancer burden.
Our ultimate goal is to identify combinations of drug targets that together may combat development of cancer drug resistance by building on our ability to identify and characterize therapy-induced rewiring of “metagenes” within high plasticity state (HPS) cells of environmentally induced mouse (and human) SCCs3. The mouse model we use is a realistic mimic of human cancer development arising after exposure to mutagens and inflammatory stimuli and resulting in de novo appearance of primary cSCCs that arise in situ but may metastasize to distant sites.
Mouse primary cSCCs can be treated in the neoadjuvant or adjuvant setting as they can easily be surgically resected. We are using this model to characterize pre-existing HPS tumor cell populations or those induced after neoadjuvant or adjuvant treatment with chemotherapeutic or immunotherapeutic drugs. We are undertaking single cell analysis of therapy-treated versus untreated carcinomas and metastases, together with analytical statistical tools developed in-house, to identify metagenes expressed in HPS cell populations and how these are enriched, depleted, and rewired after drug treatment. We are credentialing our mouse findings on HPS tumor cells in human SCCs analyzed before and during standard of care treatments. Molecular responses to therapies in the mouse model will be compared to that in the clinical setting, where each SCC type is a distinct disease entity with therapy tailored for that disease. For example, cSCC, PDL-1high lung SCC, or PDL-1+ refractory metastatic head and neck (SCCHN) are treated with anti-PD1 monotherapy, whereas pharyngeal SCCHN (like many lung SCCs and SCCHN) is treated with radiochemotherapy or immunochemotherapy. Finally, we will use a combinatorial CRISPR genetic approach to functionally validate evolutionarily conserved drug-resistance metagene candidates that, when targeted together, may prevent development of drug resistance.
Additional/final comments:
We would like to take this opportunity to thank the RAP Committee and HDFCCC for funding for this award, which has been instrumental in acquiring further federal funding.
Victor Cheuy, PhD
Assistant Professor – Physical Therapy & Rehabilitation Science
School of Medicine
Pilot for Early Career Investigators
A Musculoskeletal and Biomechanical Analysis of Diabetic, Neuropathic Foot Deformity
Awarded $ 40K – Spring, 2019
How did the RAP grant allow for further funding and/or publications?
The RAP award allowed me to establish key methodologies and analysis techniques that opened the door for several funded applications.
What was the type of follow-up funding since the initial RAP award?
The RAP award provided critical pilot data that was instrumental in enabling 1) a seed grant from the Department of Physical Therapy, 2) a seed grant from the UCSF Human Performance Center, and 3) a funded multi-site NIH R01 study
What is the focus of your research today?
My research interests focus on the unrecognized and underappreciated musculoskeletal complications in the lower extremities due to diabetes and chronic kidney disease. My work combines quantitative imaging, three-dimensional biomechanics, physical function, and actigraphy techniques.
Additional/final comments:
I'm incredibly grateful for this RAP award. Receiving it my first year at UCSF provided an incredible foundation on which I've built my first 5 years as a junior faculty in terms of establishing my lab's research direction and securing intramural an extramural funding. I'm thankful I get to continue being part of RAP now as a grant reviewer and enthusiastically support the mission of RAP.
Nadia Diamond-Smith, PhD, MS
Associate Professor – Epidemiology & Biostatistics
School of Medicine
Pilot for Established Investigators
Development of a mobile interactive education and support group intervention to improve postpartum health
in India
Awarded $ 40K – Fall, 2019
How did the RAP grant allow for further funding and/or publications?
This RAP funding was extremely useful. It allowed us to kick off a study that resulted in an R01 that is currently underway.
What was the type of follow-up funding since the initial RAP award?
The RAP funding allowed us time to build partnerships with our team in India, develop our study measures, and collect data from almost 2000 women who gave birth in the prior year. This preliminary work was instrumental in laying the groundwork for our current R01. We currently have a paper under review, 4 manuscripts in process, presented at the Population Association of America meeting, an invite only workshop on migration and health, and have submitted abstracts to several other conferences
What is the focus of your research today?
My current research focuses broadly on the intersection of women's empowerment/gender inequality on maternal and reproductive health in South Asia.
Additional/final comments:
Thank you for this funding, it has been very impactful!
Susan Fisher, PhD
Professor– Ob/Gyn, Reproductive Sciences
School of Medicine
Shared Technology Awards
Automated Detection Mode and Image Capture Software for Laser Microdissection: Enhancing the Capabilities of The Sandler-Moore Mass Spectrometry Core Facility
Awarded $ 34K – Fall, 2019
How did the RAP grant allow for further funding and/or publications?
The equipment we purchased greatly increase the functionality of our laser microdissection equipment that is used to generate samples for mass spectrometry.
Publications:
RNA profiling of laser microdissected human trophoblast subtypes at mid-gestation reveals a role for cannabinoid signaling in invasion. Development. 2021 10 15; 148(20). Gormley M, Oliverio O, Kapidzic M, Ona K, Hall S, Fisher SJ. PMID: 34557907; PMCID: PMC8572005
What was the type of follow-up funding since the initial RAP award?
We obtained additional funding from NIH, the Gates Foundation and Tobacco-Related Disease Research Program (TRDRP) that utilizes this equipment
What is the focus of your research today?
The focus of our research is still Women's Health.
Additional/final comments:
This award was greatly appreciated. Thank you!
Robert Flavell, MD, PhD
Associate Professor – Radiology
School of Medicine
Pilot Award in Precision Imaging of Cancer and Therapy (PICT)
Clinical translation of a theranostic immunoPET agent targeting CD46 in men with castration resistant prostate cancer
Awarded $ 50K – Fall, 2019
How did the RAP grant allow for further funding and/or publications?
We were subsequently awarded a translational science grant from the US Department of Defense Prostate Cancer Research Program. The preclinical results of the study were published; and the clinical study is advancing and will be published in 1-2 years.
Publications:
Wang S, Li J, Hua J, Su Y, Beckford-Vera DR, Zhao W, Jayaraman M, Huynh TL, Zhao N, Wang YH, Huang Y, Qin F, Shen S, Gioeli D, Dreicer R, Sriram R, Egusa EA, Chou J, Feng FY, Aggarwal R, Evans MJ, Seo Y, Liu B, Flavell RR, He J. Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET. Clin Cancer Res. 2021 Mar 1;27(5):1305-1315. doi: 10.1158/1078-0432.CCR-20-3310. Epub 2020 Dec 8. PMID: 33293372; PMCID: PMC7925362.
What was the type of follow-up funding since the initial RAP award?
As follow-up funding, we received a DOD translational science award from the Department of Defense Prostate Cancer Research Program..
What is the focus of your research today?
A major focus remains for the development of theranostics for imaging and treatment of cancer, with a particular focus on prostate cancer. The project, which was the subject of this award, led to a clinical trial at UCSF. We are optimistic that this method will be rolled out in multicenter trials in the future..
Additional/final comments:
The RAP grant is a wonderful mechanism to support pilot projects, and sets the stage for future high impact publications and larger grants.
Chemtai Mungo, MD, MPH, FACOG
CFAR – Traineeships in AIDS Prevention Studies Program (TAPS) Fellow
School of Medicine
Currently: UNC-Chapel Hill, Assistant Professor, Department of Ob/Gyn
Global Cancer Pilot Award
Feasibility and acceptability of the Enhanced Visual Assessment (EVA) mobile colposcope for cervical cancer screening among HIV-infected women in low-resource settings
Awarded $ 40K – Spring, 2019
How did the RAP grant allow for further funding and/or publications?
The RAP grant enabled me to obtain preliminary data that supported my K-award application.
What was the type of follow-up funding since the initial RAP award?
The RAP award led to follow-up funding for a K12 award and a foundation grant.
What is the focus of your research today?
My research continues to focus on HPV prevention among women living with HIV.
Anoop Sheshadri, MD
Assistant Professor – Medicine
School of Medicine
Family Support Award
Identifying Goals for and Barriers to Prehabilitation in Older Adults with End-Stage Renal Disease Awaiting Kidney Transplantation
Awarded $ 40K – Fall, 2019
How did the RAP grant allow for further funding and/or publications?
The initial RAP grant was extremely helpful for me, as it allowed me to gain the preliminary qualitative data I needed to launch my current research trajectory. Thus far, I only have one publication directly from that RAP grant - but I followed it up directly with an NIA R03 GEMSSTAR that has been foundational for my research platform. Furthermore, through the RAP grant, I was able to collaborate with a local community support group for kidney patients, which has been an immensely rewarding experience both personally and professionally..
What was the type of follow-up funding since the initial RAP award?
I received an R03 GEMSSTAR, which in turn provided the necessary data for my current NIH/NCATS KL-2 along with other institutional funding that has built off that. Of note, the qualitative skills I learned through conducting the RAP funded seed grant have been invaluable for my current research, as my following grants have mostly involved mixed-methods research.
What is the focus of your research today?
I am a geriatric nephrologist, and I work on improving the quality of life of older adults treated with dialysis as well as the quality of life of their care partners, primarily through improving physical function and - more recently - cognitive function.
Additional/final comments:
The RAP grants are an excellent resource to obtain funding for preliminary data or small projects and can sometimes be the necessary boost you need to reach the next level in your research career! I highly recommend looking into RAP grants, particularly for junior faculty.
Matt Springer, PhD
Professor – Medicine
School of Medicine
Pilot for Established Investigators
Potential Therapeutic Target to Limit Anthracycline-Induced Cardiotoxicity
Awarded $ 50K – Fall, 2019
How did the RAP grant allow for further funding and/or publications?
Not yet, but it is still planned. This grant started a few months before the COVID shutdowns, which threw everything into disarray. We did purchase the necessary reagents during that time, but experiments were greatly delayed. Despite that, we did accomplish the following crucial steps during the initial grant period and NCE period: We set up the cardiotoxicity model, attempted to implement it, discovered that our initial approach was problematic, arrived at an alternate way of implementing the model, and showed that the alternate approach was an effective way to get the cardiotoxicity state that we needed for subsequent therapeutic experiments. For reasons of personnel and grant funding cycles, we had to focus on other things for a while, but the therapeutic experiment remains on our agenda, and in fact, is one of the experiments being actively planned for the next half-year. Success in that experiment will enable our applications for extramural funding and further research.
What was the type of follow-up funding since the initial RAP award?
As described above, we don't have it yet, but applying for an NIH grant is planned if we get good results.
What is the focus of your research today?
Other than still planning the last experiment from this RAP project, our main focus is comprised of studying the effects on vascular and cardiac function of smoke and vaping aerosol for tobacco and marijuana products in rats, studying how these types of smoke and aerosol exposures influence the amount of heart tissue that remains alive after an induced myocardial infarction, determining therapeutic potential of anti-sense oligonucleotides that target pathological microRNAs in heart failure models, and a clinical study of vascular function in marijuana users.
Additional/final comments:
This RAP grant was very much appreciated as it opened the door for these studies, given that we had no prior experience with anthracycline cardiotoxicity. Despite the monkey-wrench thrown into the process by COVID, it will still ultimately let us know whether this, our proposed therapeutic approach, has potential and is worthy of further study. An additional benefit of the seed-grant enabled us to do the experiments that provided a Pharmacy student with her curricular research project.
Li Zhang, PhD
Professor – Medicine
School of Medicine
Re-entry Award
Using Machine Learning to Better Characterize and Understand the Clinical Prognostic Features and Landscape of Immunosequencing
Awarded $ 30K – Spring, 2019
How did the RAP grant allow for further funding and/or publications?
The RAP grant enabled support for an analyst to assist me with further generation of preliminary data.
What was the type of follow-up funding since the initial RAP award?
I received two awards, an NIH R21 and NIH R01 in 2021 and 2022 respectively.
What is the focus of your research today?
My current research focuses on developing bioinformatics tools for high-throughput sequencing data for cancer research, especially for the next data generation sequencing of the immune repertoire.
Additional/final comments:
This award was greatly appreciated. Thank you!