Research Projects Funded by MCCRF

2024 Grants

mccrf scientific research grant

Matthew Dietz, PhD Candidate, University of Minnesota “Improving Immune Checkpoint Inhibitor Therapy by Inhibiting Microbial Communication”.

The bacteria in the gut (the gut microbiome) communicate by accumulating chemical signaling molecules that regulate their ability to activate processes involved in disease onset and progression. This communication is termed quorum sensing, and the enzymes that degrade these signaling molecules are known as quorum quenching (QQ) enzymes. Our lab is one of the first to use these enzymes as a therapeutic colorectal cancer (CRC) treatment, and our preliminary data is promising. I will continue examining their therapeutic potential in this coming year, looking at whether they can be used to improve tumor response to immune checkpoint inhibitor (ICI) therapy. ICI therapy, while powerful, can only affect tumors with high microsatellite instability (MSI-H), which account for less than 8% of late-stage CRCs. Tumors suppress the immune system, and ICI therapy hopes to inhibit this suppression to allow the body to destroy the tumor. In microsatellite stable (MSS) tumors, this inhibition is not enough. There is growing evidence, however, that the immune suppression associated with CRCs is caused, in part, by disruptions of the gut microbiome. I hypothesize that disrupting this problematic microbiome behavior using our QQ enzymes may result in MSS tumors becoming more susceptible to ICI therapy. I plan to test this using a CRC mouse model, testing response to ICI therapy with and without QQ enzyme-treated water over a two-month period. I am only able to do this thanks to the generosity of the MCCRF and its donors, and from the bottom of my heart, thank you. Without your support, researchers like myself would not be able to do what we do and work towards saving lives.

norm and pat wells memorial grant

Travis Gates, PhD Candidate, University of Minnesota “Targeting LAT1 for Metabolic Intervention in Colorectal Cancer”.

Colorectal cancer (CRC) remains one of the most prevalent cancers worldwide and is the second leading cause of cancer-related mortality in the United States. CRC Tumor growth heavily relies on the availability of nutrients and essential amino acids to support sustained cell proliferation. Our previous investigations showed increases in essential amino acids (eAAs) in CRC tumor tissues compared to matched normal adjacent tissues. eAAs cannot be synthesized by the host and the observed eAA enrichment could be supported by the gut microbiota. The SLC7A5 gene, encoding the LAT1 amino acid transporter, is pivotal in facilitating metabolicpathways associated with cancer by supplying tumor cells  with essential amino acids. We observed elevated expression of the LAT1 CRC compared to matched normal adjacent tissues. Furthermore, we saw increased LAT1 expression in microsatellite-stable (MSS) tumors compared to the microsatellite instable-high (MSI-H) subtype. Additionally, LAT1 expression increases as tumors progress from adenoma to malignant disease. Here, we examined the impact of inhibiting LAT1 on cellular metabolism in vitro and tumor growth in vivo. We show that inhibition of LAT1 reduces cell proliferative capacity in CRC cell lines and CRC organoid models. We have shown that LAT1 inhibition results in reduction in oxidative capacity and overall alterations in cellular metabolism. Lasty, we show that LAT1 inhibition delays CRC tumor growth in vivo and may stimulate an immune response against CRC. This study aims to show how LAT1 inhibition can be utilized along with immune checkpoint inhibitors in an advanced stage CRC mouse model. Successful completion of this project can inform translational combination therapy approaches to improve CRC patient outcomes.

peter wilhoit memorial grant

Renzo E. Veras, PhD, Post Doctoral Research Fellow, Mayo Clinic “Novel Therapeutics for RAS Mutant Colorectal Cancer".

RAS mutations are major tumor drivers in advanced colorectal cancer (CRC). Given the fact that signaling molecule SOS1 is essential for RAS activity, and it is overexpressed in CRC with minimal expression in surrounding normal tissues, it represents an attractive target to treat advanced CRC. We recently successfully developed a novel SOS1 degrader which showed promissory chemical properties. In this project, we propose use human CRC models to translational significance of SOS1 degrader for mutant RAS CRC. We will also explore potential resistance mechanisms that CRC cells could develop for our degraders. The new information that will be provided by this proposal will offer a novel therapeutic strategy to target tumors with minimal off-target toxicity and help improve outcomes of patients with mutant RAS CRC.

sarah debord memorial grant

Arjun Gupta, M.D. Assistant Professor, Medical Oncology, University of Minnesota. “COLLABS - COLorectal Cancer Legal and Administrative Burden Support: A Pilot Clinical Trial”.

Persons with colorectal cancer face considerable legal and administrative challenges as they navigate the complex health system. This causes psychological and financial distress to patients, and leads some patients to even abandon cancer treatment. In a study of patients with colorectal cancer, more than 70% experienced major financial hardship (defined by events such as selling one’s home) within one year of diagnosis. Cancer Legal Care (CLC) is a nonprofit that provides free legal services to persons with cancer. CLC provides assistance with insurance coverage and denials, Social Security benefits, employment, disability, housing concerns, debt management, and will and estate planning, among other issues. In a survey of CLC clients, 93% responded that CLC was able to resolve their legal issue(s). However, there is currently no structured pathway for patients to access these services proactively.

Our primary goal is to conduct a clinical trial to determine the feasibility and acceptability of providing free and early legal services to 20 patients with colorectal cancer receiving care at the University of Minnesota. CLC representatives will meet with patients one-on-one (a ‘’legal care check-up’’) to review their situation and concerns, screen for additional issues, develop an individualized care plan, review and provide necessary services, and serve as a longitudinal point of contact. We will examine the impact of CLC services on patient-reported measures of stress, coping ability, financial burdens, and quality-of-life. At the end of study, we will interview patients, oncologists, and CLC staff to adapt and refine the intervention. The results will allow us to advocate for expanding access to legal care services - including addressing capacity, incentive, and implementation problems - for patients with cancer. 

mccrf symptom and survivorship research grant

Ajay Prakash, MD, PhD, Assistant Professor, Medical Oncology, University of Minnesota. “A pilot trial of probiotic supplementation during adjuvant chemotherapy for stage III colon cancer”.

Despite advances in the treatment of colon cancer over the past two decades, individuals diagnosed with stage III colon cancer continue to receive largely the same post-surgical chemotherapy, which is associated with meaningful toxicity, along with social and financial challenges. Thus, there is a need for alternative treatments which can improve colon cancer patient outcomes and potentially reduce treatment-associated side effects. While a variety of supplements have been evaluated in this setting, only probiotics have demonstrated promising effectiveness in limited human trials. Our project will extend these prior studies and establish the potential benefit of probiotic supplementation in combination with standard of care treatment in colon cancer.

Over the coming year, we will provide access to a small cohort of patients undergoing routine treatment to our randomized trial and evaluate their treatment tolerance and cancer-associated outcomes. Based on existing literature, we anticipate that they may experience less nausea and gastrointestinal distress than patients without supplementation. We will also study the patients and their cancers to understand the potential mechanisms by which these benefits may be accrued. At the conclusion of our pilot study, we hope to expand our work into a full-scale clinical trial supported by the NIH. We hope that this ongoing research will benefit patients with colon cancer by providing them with an inexpensive, readily accessible treatment which can support them as they undergo the immense challenge of cancer treatment.

2023 Grants

The Sarah Debord Memorial Grant

Arjun Gupta, M.D. Assistant Professor, Medical Oncology, University of Minnesota. “Characterizing the Time Toxicity of Cancer Care Among People Living with Colorectal Cancer”.

Patients with cancer spend a substantial amount of time on medical care. We conceptualize these time demands as the “time toxicity’’ of cancer care. Patients with colorectal cancer are particularly vulnerable given that chemotherapy is often administered over multiple days, and patients can experience burdensome symptoms and complications. Our research group uses mixed (qualitative and quantitative) methods to investigate time toxicity. We interview patients, care partners, and clinicians to understand their experiences. We analyze objective time burdens faced by patients. This data helps improve cancer care (e.g., bunching appointments to save trips), influences clinical trials (e.g., so trials report the time toxicity of new drugs), and promotes innovation (e.g., home-based care). As a medical oncologist and health services researcher, I use this data to achieve my long-term goal to minimize the time burdens of cancer care, so patients can spend more of their precious time where and how they want.

Norm and Pat Wells Memorial Grant

Matthew Dietz, Graduate Student, University of Minnesota “Quorum Quenching as a Therapeutic Lead for Colorectal Cancer”.

Various gut bacteria are associated with an elevated risk of colorectal cancer (CRC) and a reduced success rate of certain cancer treatments. These bacteria communicate to one another by releasing chemicals in a process called quorum sensing. In fact, some new research has shown that this communication happens between our cells and our gut microbiome as well, encouraging metastasis in colorectal cancer. Our research aims to use enzymes that degrade these communication signals to examine the effects this may have on CRC growth and metastasis in a mouse model. If we can determine what role these communication signals play in cancer development and metastasis, we may be able to use these enzymes as an addition or alternative to existing cancer therapies.

Peter Wilhoit Memorial Grant

Christopher J. LaRocca, M.D. Assistant professor, Surgical Oncology, University of Minnesota and Minneapolis VA Medical Center “Novel Adenovirus-Based Combination Therapies for Colorectal Cancer Treatment”.

Our research group’s main area of investigation is in the use of oncolytic viruses for the treatment of cancer. By modifying an adenovirus (a virus that typically causes common cold symptoms), it can be targeted to selectively infect, replicate within, and kill specific types of cancer cells. In addition, these oncolytic adenoviruses can be designed to express genes at the local tumor site. One such gene is the sodium iodide symporter (NIS), which can be used to facilitate cancer imaging and therapy when combined with radioactive iodine. Our main project is using the NIS-expressing adenovirus to develop a novel treatment regimen for patients with metastatic colorectal cancer.

2022 Grants

norm and pat wells memorial grant

Dechen Wangmo, PHD Student, University of Minnesota “Role of Tumor Cell-Intrinsic Factors in Colorectal Cancer Immune Evasion”

The poor response of most colorectal cancer (CRC) patients to immunotherapy is a major unmet clinical need. Immune evasive mechanisms and lack of a suitable preclinical model that recapitulates human CRC condition underlie the unfavorable response to immunotherapy. To overcome these challenges, I generated mouse tumor organoids modeling Apc-/-, KrasG12D, P53-/-, and Smad4-/- mutations, which are co-mutated with high frequency in advanced CRC. Using CRISPR screening and integrative immune score analysis, I identified CEP55 as a potential target to sensitize the tumor to immunotherapy. Previous studies have shown that CEP55 is overexpressed in other cancers such as breast cancer but its role in CRC is unknown. This research will elucidate how CEP55 promotes tumor progression and immune evasion using tumor organoids.

peter wilhoit memorial Grant

Travis Gates, PHD Student, University of Minnesota “Macrophages as Regulators of Tumor Immunity in Colorectal Cancer” 

Colorectal Cancer (CRC) possesses unique pathological characteristics due to a complex microbiome in the tumor microenvironment (TME) comprised of diverse bacterial species and metabolites, which can alter the activity and function of infiltrating immune cells. Understanding regulatory mechanisms by which the microbiome and its metabolites alter macrophage phenotype and function can lead to novel therapeutic strategies towards increasing tumor-infiltrating T cells, which could expand immune checkpoint inhibitors (ICIs) treatment to more CRC patients. We have found correlations between macrophage subtype and essential amino acid abundances in patient tumor and matched normal tissues from RNA-sequencing, 16S sequencing, and metabolomics. We are currently investigating diagnostic methods to track essential amino acid abundances in stool samples to monitor CRC recurrence. Additionally, we are investigating in vivo tumor models that target essential amino acid transport to see if inhibition of essential amino acid transport can promote immunogenic macrophage subtypes which can synergize with current generation ICIs.

2021 Grants

Dr. Xianda Zhao, University of Minnesota - "The immune regulatory effects of tumor-derived extracellular vesicles in colorectal cancer"

Dr. Elizabeth Adamowicz, University of Minnesota - "Impact of host-microbiome metabolic exchange on colon cancer development"

Glancis Luzeena Raja Arul, Mayo Clinic - “Modeling Adaptive Therapy for Metastatic Colorectal Cancer”

2020 Grants

Dr. Alessia Stornetta, University of Minnesota - "Identification of risk to colorectal cancer using molecular DNA damage profiling from the E. coli-produced genotoxin colibactin in colonoscopy samples"

Dr. Mahendra Pal Singh, Mayo Clinic - "Epigenetic mechanisms of colorectal cancer tumor promotion by Parvimonas micra, an opportunistic pathogenic bacterium of the oral cavity"

Mr. Xianda Zhao, University of Minnesota - "Functions of Atypical Chemokine Receptor 4 (ACKR4) in Anti-tumor Immunity in Colorectal Cancer"

2019 Grants

Dr. Brooke Druliner, Mayo Clinic - "Characterizing telomere and chromatin dynamics in colorectal transformation"

Dr. Seung Ho Shin, The Hormel Institute, University of Minnesota - "Discovery of β-catenin inhibitors for treatment of colon cancer"

2018 Grants

Dr. Rentian Wu, Mayo Clinic - "Targeting the mutant KRAS- or BRAF-induced enhancer as an approach to overcome resistance to 5-fluorouracil−based chemotherapy in colorectal cancer"

Dr. Mizuho Sato-Dahlman, University of Minnesota - "Treatment of metastatic colon cancer by cancer stem cell-targeted oncolytic adenovirus"