January 6, 2021

Inaugural Endeavor Award Recipients Announced

Commitment to team science bolstered with $8 million in awards. Online portal for new Endeavor awards is now open.

The Mark Foundation for Cancer Research announces the first recipients of its Endeavor Awards and that the online portal for new Endeavor awards is now open (www.themarkfoundation.org/endeavor).

The inaugural Endeavor projects focus on three particularly intractable problems in cancer research: preventing and overcoming metastasis, decoding the whole-body response to cancer, and understanding the molecular mechanisms of tumor plasticity and progression.

The Mark Foundation Endeavor Awards were created to unite scientists with diverse areas of expertise to address urgent questions in cancer research. This collaborative program enables teams of investigators — working either within a single institution or across multiple organizations — to tackle research challenges in cancer that are too complex for an individual lab to address on its own.

“Collaboration is key to success in science,” says Michele Cleary, PhD, Mark Foundation CEO. “Our funding brings together investigators who are passionate about solving a common problem with very complementary capabilities and expertise that, when deployed together, accelerate the discovery of new knowledge and solutions.”

Recipients of the inaugural Endeavor Awards include a team at the University of California, San Francisco (UCSF); a team at Cold Spring Harbor Laboratory (CSHL); and a multicenter team of investigators from Columbia University, Memorial Sloan Kettering Cancer Center, and Johns Hopkins University School of Medicine.

Understanding and Eliminating Metastatic Cancers

The team from UCSF comprises six scientists with expertise in wide-ranging disciplines working together to better understand the “rulebook” of metastatic cancer, with the goal of developing therapies to prevent or eliminate it.

Metastasis is the greatest challenge faced by people with cancer. In fact, about 90% of cancer deaths can be attributed to metastatic disease rather than the patient’s primary tumor. Metastasis originates when individual cancer cells spread to other tissues and survive to establish secondary tumors, which are often more resistant to therapy than the original tumor.

Until now, our understanding of metastasis has been limited by difficulties in determining where, when, and how tumor cells interact with other tissues as they spread. With this project, the investigators aim to get at the roots of metastasis using single-cell analysis and a “multi-omic” approach (including genomics, epigenomics, transcriptomics, and proteomics) to study different subsets of tumor cells, including cancer stem cells, from model systems.

“Metastasis is kind of a perfect storm,” said Jeroen Roose, PhD, professor and vice chair in the UCSF Department of Anatomy and co-founder of the UCSF Bakar ImmunoX Initiative. “We know that cancer cells leave tumors all the time, but only rarely do they metastasize. If we understood the rulebook of metastasis, we could look at a patient’s cancer and be able to predict when or how their particular tumor is going to metastasize. It would be an amazing breakthrough.”

This project aims to boost the understanding of tumor heterogeneity in the metastatic setting, which will help untangle how certain tumor cells gain the ability to spread and thrive in new environments. It is also focused on understanding the role that tumor–host interactions play in metastasis, including elements in the tumor microenvironment that promote the emergence of metastatic cells, the role of the immune system, and how tumor–nerve interactions in the extracellular matrix are associated with tumor aggression. The investigators are also using organoid and animal models to identify vulnerabilities in metastatic tumor cells, to ultimately apply those findings to develop new strategies for therapy.

The six investigators on the UCSF team are Eric Collisson, MD, Department of Medicine, Division of Hematology/Oncology; Jay Debnath, MD, PhD, Department of Pathology; Andrei Goga, MD, PhD, Department of Cell and Tissue Biology and Department of Medicine; Sarah Knox, PhD, Department of Cell and Tissue Biology; Jeroen Roose, PhD, Department of Anatomy and Co-Founder of UCSF Bakar ImmunoX Initiative; and Valerie Weaver, PhD, UCSF Center for Bioengineering and Tissue Regeneration, Department of Surgery.

Decoding the Host Response to Cancer

The CSHL team is focused on decoding the complicated whole-body response to cancer. The aim of this research is to uncover the systemic biological changes that can occur throughout the body after cancer develops.

Eventually the researchers want to gain a deeper understanding of the interactions between cancer cells and other tissues in the body to connect the behavioral, neuroendocrine, metabolic, microbiome, and integrated immune responses that occur during cancer progression. They will start with mouse models, then apply the learnings to human cancer.

“Cold Spring Harbor Laboratory has initiated a major new program in whole body physiology focused on understanding brain-body interactions,” said Bruce Stillman, PhD, President and CEO of Cold Spring Harbor Laboratory. “An important component of the initiative is to understand how cancer impacts our physiology, and I am very pleased to collaborate with The Mark Foundation via its support of Tobias Janowitz and Semir Beyaz. These investigators have very exciting research programs that will be greatly enhanced with the support of The Mark Foundation.”

Although cancers traditionally have been classified by the tissue in which they originate, cancer is a systemic disease that can affect many parts of the body. This is particularly true for epithelial cancers, such as colorectal, lung, pancreatic, and renal cancers. One example of the systemic effects of cancer is cachexia, a wasting syndrome common in patients with advanced disease. Cancer can also have a wide-ranging influence on other aspects of the human experience such as sleep and metabolism.

The first part of this effort is aimed at studying the wide-ranging, systemic effects of cancer, including the interactions of cancer with the host’s neuroendocrine system, immune system, and microbiome. The investigators are using experimental animal models and patient samples in their research. They expect this approach to be synergistic, using the same samples to study a range of different connections so that the resulting data can be more easily integrated across experiments.

The data collected from this project can be used to develop organ system-specific cancer models, which then can be used to build translational models of potential host response. These models have implications for predicting disease outcomes and response to treatment in patients.

The CSHL team is led by Semir Beyaz, PhD, Donaldson Translational Fellow and Cancer Center Member, and Tobias Janowitz, MD, PhD, Assistant Professor and Cancer Center Member.

Molecular Mechanisms of Tumor Progression and Plasticity

Investigators from three major East coast cancer centers have teamed up to study how cancer cells change their fate with an emphasis on how this lineage plasticity drives the progression of bladder cancer.

Bladder cancer can manifest in two forms. The more prevalent form, non-muscle invasive bladder cancer (NMIBC), has a better prognosis, whereas the less common form, muscle-invasive bladder cancer (MIBC), is associated with poor clinical outcomes. These two types of bladder cancer were once considered distinct diseases, but recent studies employing advances in genetic analysis and genetically engineered mouse models suggest that bladder cancer can progress across a continuum from NMIBC to MIBC.

Lineage plasticity, a cell’s ability to change from one cell fate to another, appears to play a central role in this progression. Team members have demonstrated that epigenetic reprogramming may serve as the critical mediator of tumor cell lineage plasticity. Substantial progress has been made in recent years in targeting epigenetic regulators for cancer therapy, providing hope that these studies could eventually lead to new treatment options for bladder cancer patients.

Through this project, the researchers aim to gain a better understanding of the molecular mechanisms regulating lineage plasticity in bladder cancer through the integration of their complementary clinical and translational medicine expertise. A defining component of their research is an ambitious multi-site plan to apply cutting-edge histopathological, genomic, and computational methods to the characterization of a unique prospective cohort of longitudinal bladder cancer samples obtained from patients whose cancer has progressed from NMIBC to MIBC.

The investigators anticipate that findings from their research will lead to better methods for identifying patients at elevated risk of progressive disease, thereby improving clinical outcomes by enabling new clinical trials and providing therapeutic options for better treatments of early-stage bladder cancer patients.

Members of the project team are Cory Abate-Shen, PhD, and Michael Shen, PhD, of the Herbert Irving Comprehensive Cancer Center at Columbia University; David Solit, MD, of Memorial Sloan Kettering Cancer Center; and David McConkey, PhD, of Johns Hopkins University School of Medicine.

About The Mark Foundation Endeavor Awards

When selecting the teams to receive the first Endeavor Awards, Mark Foundation leadership looked for multidisciplinary, collaborative projects that brought investigators together to begin exploring important questions in cancer research. These projects address issues that have the potential to ultimately drive significant improvements in the lives of people with cancer.

One goal of the Endeavor Award program is to plant seeds for research projects that could eventually lead to even bigger projects that could be funded by The Mark Foundation.

“When selecting these first recipients, we sought out projects that wouldn’t get funded by other sources,” Cleary says. “With this program, we’re willing to take more risk and get on board with scientists who have great ideas.  And we want to make sure that the scientists who we’re funding have all of the resources they need to move forward — and to do that at an accelerated pace.”

The Letters of Intent Online Portal for Endeavor Awards is now open. Letters of Intent are due March 1. For more, visit www.themarkfoundation.org/endeavor.

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