Eleven Cancer Research Projects Funded in Spring 2022 RAP Cycle

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

Our project is focused on understanding the immune signals that promote tumor formation in the developing liver. Our proposal is focused on implicating specific macrophage-dependent mechanisms that, when dysregulated, promote hepatoblastoma.

What motivated you to pursue this particular project? What do you find most exciting about this research?

As a pediatric liver surgeon, I am focused on improving the care of infants and children with liver tumors. This research project takes a step forward to identify targetable mechanisms to treat hepatoblastoma (HB). From a scientific perspective, it is fascinating to consider how tumors form in a developing tissue and to begin dissecting the mechanisms that maintain tissue homeostasis and promote tumor growth.

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

We are evaluating the feasibility of using a new communication tool that we adapted for geriatric oncology called Best Case/Worst Case-Geriatric Oncology. We will learn how medical oncologists use this communication tool during decision-making conversations with older adults with advanced cancer and their families. We want to understand oncologist, patient, and caregiver perspectives on the communication tool and how it might support older adults and their families in making goal-concordant cancer care decisions.

What motivated you to pursue this particular project? What do you find most exciting about this research?

My geriatric oncology research program is focused on solving challenges that I’ve encountered during my own clinical practice as a medical oncologist caring for older adults with lung cancer. Older adults, especially frail older adults, are often not included in cancer clinical trials. This underrepresentation results in a lot of uncertainty about the potential benefits and harms of different treatment options when we talk to older patients and their families about treatment options. The Best Case/Worst Case-Geriatric Oncology communication tool helps oncologists acknowledge this uncertainty and describe a range of plausible outcomes, tailored to the specific patient. I am most excited to teach this framework to oncologists and see how it changes their decision-making conversations with older patients.

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

Digitization of stained tissue sections using whole slide scanners has transformed traditional histology workflows by enabling high throughput, precise imaging of histological slides. To this end, the Zeiss Axioscan in the Histology and Biomarker Core has performed very reliably for whole slide scanning, specifically for multiplexed biomarker detection using immunofluorescence (IF) imaging. The focus of our project is to upgrade its illumination system with a state-of-the-art light-source and accompanying spectral unmixing software. The enhancement will increase the efficiency and quality of our highly valued IF scanning services.

What motivated you to pursue this particular project? What do you find most exciting about this research?

While the existing light-source (SpectraX) was the most advanced illumination system available when purchased, it has a significant limitation, as a third-party vendor (Lumencor), of only partial operation by Zeiss's image acquisition software and cannot be operated for individual excitation wavelengths for a specific fluorophore detection, increasing the chance of non-specific excitation of the multiplexed fluorophores. Such cross-talks between channels increase with the number of fluorophores in the panel. This limitation motivated us to search for better alternatives.

The acquisition of the Zeiss Colibri7 LED illumination system with selectable narrow-band illumination that reduces cross-excitation and high efficiency coupling of LEDs to sample plane for greater illumination intensity is a very significant improvement for increasing biomarker specificity in the images with greater detail. The system covers the excitation spectrum with seven channels from UV to near-infrared (385nm-775nm) with selectable LEDs where each illumination intensity, depending on the sensitivity of the sample, can be rapidly adjusted in microseconds by the Zeiss system control software. The acquisition will essentially transform the current scanner to a state-of-the-art imaging platform. The most exciting feature is its compatibility to the image acquisition software, which makes it easier to program an individual LED for a particular fluorescent probe. Overall, Colibri7 LED illumination system will optimize both the efficiency and quality of the scanned images generated by the Zeiss AxioScan whole slide scanner.

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

The eNET study is a digital health study to investigate quality of life for patients with neuroendocrine cancers. Although neuroendocrine cancers are often indolent, patients can have many chronic symptoms from tumor bulk/metastasis, hormone overproduction, and the cumulative side effects from prolonged treatment. In eNET, participants are asked a series of validated surveys over time about symptoms, lifestyle, diet, exercise, quality of life, medical expenses, and financial toxicity. We hope to better characterize patterns of symptoms and identify risk factors for high symptom burden in this population. The RAP grant will fund the analysis of the baseline and 6-month study visit data. 

What motivated you to pursue this particular project? What do you find most exciting about this research?

Neuroendocrine cancers are relatively rare but increasing in incidence. We have more treatment options than ever before, but many patients I see in clinic still struggle with quality of life. The eNET study is unique because 1) we are measuring quality of life using validated surveys, which are reliable, reproducible, and allow for comparisons between different groups; and 2) the longitudinal component, which I hope will better capture the full experience of living with these cancers. I'm also learning how to conduct web-based research and engage participants remotely, an approach that may have promise for studying other rare cancers in the future!

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

The focus of this application is diffuse midline gliomas, pediatric tumors that are difficult to resect because they occur in the midline structures of the brain. In this study, we will apply single-cell and spatial multi-omics approaches to rare clinical specimens. Our goal is to elucidate the epigenetic mechanisms that diffuse midline gliomas exploit to drive treatment resistance.

What motivated you to pursue this particular project? What do you find most exciting about this research?

We've recently developed single-cell epigenetics assays which will provide insights into cancers, such as diffuse midline glioma, that are driven by mutations in genes that regulate chromatin structure. Until now, my lab has largely focused on adult brain tumors. So, I'm excited about the opportunity to expand our research into pediatric cancers.

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

In contrast to the USA, morbidity and mortality related to colorectal cancer is rapidly increasing in Mexico. The introduction of colorectal cancer screening linked to comprehensive diagnostic and treatment services will be essential to meet this challenge. This RAP award will provide resources to support the development of one of the first such programs for government workers and retirees in Mexico.

What motivated you to pursue this particular project? What do you find most exciting about this research?

For the last 5 years, I have worked closely with the UCSF Global Cancer Program and our partners in Mexico on research to support the introduction of colorectal cancer screening in Mexico. Our team has documented the increasing burden of colorectal cancer, the resources needed to address the problem, and we have pilot tested several small but successful screening programs. This project will be the first colorectal cancer research project to be completed in full partnership with an integrated health system in Mexico that has the stated goal of creating a scalable and sustainable model for colorectal cancer control that can be replicated in other health systems across Mexico. Equally exciting, the implementation of the project will be supported by UCSF trainees working in close collaboration with researchers from the Instituto Nacional de Salud Pública and Instituto Nacional de Cancerología in Mexico.

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

This project seeks to understand the impact of telehealth use to provide cancer care to older adults with both cancer and cognitive impairment. The need for rapid expansion of telehealth during the COVID19 pandemic means the way teleoncology care is delivered is not necessarily well-suited to meet the needs of more vulnerable patients. Now that telehealth has become a fixture in oncology care delivery, it is important to understand how we can adapt and improve care delivery to meet the unique needs of highly vulnerable patients with both cancer and cognitive impairment. In this study, we will conduct one-on-one interviews with older patients with cancer and cognitive impairment, their caregivers, and the healthcare professionals caring for them to understand what the barriers to care are and how we can improve the delivery of cancer care via telehealth to this population.

What motivated you to pursue this particular project? What do you find most exciting about this research?

This project was very much motivated by real-life challenges that arose during the COVID19 pandemic, when I switched to “seeing” most of my older cancer patients, many of whom have challenges with memory or managing complex information, via phone or video visits. Cancer care often involves a lot of in-depth discussions with visual aids, logistical coordination of labs/scans/treatments, complex medication regimens, and need for timely accurate information exchange, all of which are harder when delivered via telehealth, particularly for patients who have cognitive problems or cannot manage video visits. I encountered new problems and challenges every day as I cared for my patients and then had to figure out how to adapt the way I provided care to this new reality, and I realized each provider was individually going through the same thing. So I thought it would be a good idea to gather information systematically about what the challenges are so we can take the next step of collectively figuring out how to improve the way we provide care. The most exciting thing about this research is that it has the potential to transform how we care for some of our most vulnerable patients.

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

Radioligand therapy is an emerging technology in which radiation is selectively targeted to tumors using molecular targeting, enabling effective tumor treatment with minimal toxicity in many cases. When paired with high-quality PET imaging agents utilizing the same targeting agent, this method allows physicians to “see what they treat,” using the theranostic strategy. In particular, targeted alpha therapy (TAT) using radioimmunotherapy may be employed to deliver very high doses of highly lethal alpha particles to tumors. In this method, highly specific targeting immunoglobulins labeled with alpha emitters such as 225Ac are administered, which are highly effective for tumor control. We have developed a highly effective TAT agent, 225Ac-DOTA-YS5, for the treatment of prostate cancer, and verified its activity in prostate cancer models. This agent targets CD46, an antigen that is highly expressed in prostate cancer, among other malignancies. YS5 is a clinical stage antibody that we have developed and brought to multiple clinical trials (NCT03575819 and NCT05011188 for mCRPC, and NCT03650491 for multiple myeloma). However, because YS5 is a full-length human IgG1, current YS5-based TAT agents have a long-circulating half-life, which may raise the concern of off-target toxicity. Increasing the ratio of tumor to normal tissue radiation delivery is a central goal for the development of radionuclide therapies, to maximize therapeutic effect while minimizing toxicity.

What motivated you to pursue this particular project? What do you find most exciting about this research?

While targeted radioligand therapy shows excellent treatment efficacy in both preclinical and clinical settings, there are concerns of off-target toxicity due to the long biological half-life of targeting agents such as antibodies, nanoparticles, and liposomes. In recent years, linker chemistry methodology has made notable progress in the antibody-drug conjugate field, by improving pharmacokinetics via reduction of off-target toxicity with slow release of cytotoxic payloads at targeted sites. More recently, this strategy has been investigated in the radioligand therapy field. In my previous work, PEGylated antibody (Trastuzumab) with short PEG linkers were shown to accelerate blood clearance with higher tumor uptake which leads to improved tumor-to-organ ratios. We hypothesize that it is likely reflect metabolic instability of the linker, yielding small fragments which are rapidly cleared from circulation. At least one agent incorporating such a linker, [225Ac]FPI-1434, is now in clinical trials (NCT03746431). All taken together, the prior and ongoing work implies that the insertion of a properly selected linker between an antibody and cytotoxic payload reduces the non-specific toxicity as compared to non-linker conjugates in radioimmunotherapy.

The most exciting part of this research is the use of novel linker technology to connect the therapeutic radioisotope 225Ac with the highly specific targeting antibody YS5 for the treatment of prostate cancer. This strategy will maximize the therapeutic benefit and minimize toxicity. 

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

I am developing an antibody-based therapeutic that targets a protein named xCT. This protein is expressed by most advanced or poor prognosis solid tumors, but is expressed by few normal cells in the body. Inhibition of xCT function or expression can kill tumor growth in vitro and in animal studies, making this a very promising therapeutic target. My group previously performed several different screens of a phage display nanobody library, and selected a panel of these antibody fragments that specifically identify xCT. I am now working with Dr. Ashworth’s group to identify and optimize nanobodies from one of our screens – to identify those with the best ability to block xCT function. Generous funding from this RAP award will allow me to also independently assess promising nanobodies from our other library screens, and to also test these nanobodies for their ability to block xCT function. Ultimately, the most potent set of blocking nanobodies will be lead compounds for an xCT targeted therapeutic.

What motivated you to pursue this particular project? What do you find most exciting about this research?

I originally identified this xCT in analysis that contrasted features of a large panel of breast cancer-derived cell lines against features of non-tumorigenic breast cell lines. I found that xCT was primarily expressed on and required by cancer cell lines derived from the poor prognosis, triple negative subset of breast cancer. Patients with this tumor type have few therapeutic options, thus the need for a specific therapeutic is acute. Subsequent research by several other investigators has revealed a requirement for xCT expression on advanced and poor prognosis subtypes of many other solid tumors, suggesting that an xCT-targeted therapeutic could be used to treat many different types of advanced cancer.

What could possibly be a more rewarding career than developing a drug that could help cancer patients overcome their disease? I cannot think of anything more exciting or rewarding, and I wake each morning eager to see what the day’s data will show.

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

Targeted radiotherapy (TRT) is a treatment approach in which a radioactively labeled drug (e.g. small molecule, antibody) administered intravenously to a patient delivers ionizing radiation to treat multiple tumors within the body simultaneously. Although not a new therapeutic strategy (radioiodine has been used for decades to cure a form of thyroid cancer), TRT is currently undergoing a clinical renaissance that has resulted in several recent FDA approvals in the past 10 years, including Lutathera for neuroendocrine tumors, Azedra for pediatric malignancies, and in 2021, Pluvicto for metastatic castration resistant prostate cancer (mCRPC). This project aims to develop a first in class TRT that is selectively activated by a protease unique to the tumor microenvironment. After activation within the tumor, the TRT binds durably within the tumor via a special interaction with the tumor cell membrane. 

What motivated you to pursue this particular project? What do you find most exciting about this research?

Although there is a swell of enthusiasm to revisit TRT as a treatment option for metastatic cancers, TRTs are rarely curative, and patient responses are often variable and transient. These observations are somewhat puzzling, given that patients are preselected for TRT based on evidence for high tumoral target expression on a PET scan, and ionizing radiation is an extremely effective antitumor agent with few known tumor resistance mechanisms. The founding hypothesis of this project is that poor tumor responses can be attributed in part to faulty approaches to tumoral delivery of radioisotopes. Our project aims to address this unmet need through the novel delivery strategy articulated above. Excitingly, we can rapidly translate our findings into the clinic, as the pathway to clinical translation for radiopharmaceuticals is significantly more straightforward than many other drug classes.

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

Nanomedicines, nanoparticles/ liposomal/ pegylated drug formulations, are increasing in prevalence for the delivery of therapeutic payloads to tumors. We will tag a star-PEG, 4-armed 15-20nm PEG polymer carrying the PARP inhibitor Talazoparib, with a positron emitting radioisotope zirconium-89 (3.3 day half-life) to show the tumor and non-tumor temporal distribution in preclinical prostate tumor models. We will evaluate the radiolabeled PEG as a potential companion diagnostic agent that may be used to forecast therapeutic delivery to the tumor in advance of giving the therapeutic dose. This is an example of image-guided drug delivery where we see that the star-PEG accumulates in the tumor then treat it.

What motivated you to pursue this particular project? What do you find most exciting about this research?

We have been working with our collaborators at Prolynx to demonstrate that star-PEGs, small nanopolymers, are capable of passive delivery of chemotherapeutic agents to tumors. We will collect requisite data to support an Investigational New Drug submission to the FDA to permit the evaluation of radiolabeled star-PEGs in human subjects.