read-more
Read more about Fred Hutch achievements and accolades.
Two Fred Hutch Cancer Center researchers have recently been awarded multi-year research grants from the V Foundation for Cancer Research.
Michael Haffner, MD, PhD, associate professor in the Human Biology and Clinical Research divisions, received a V Foundation All-Star Grant providing $1 million in research funding over 5 years. Haffner will study how a specific change to DNA in cancer cells could result in new therapeutic targets for FDA-approved cancer drugs.
Kevin Cheung, MD, associate professor in the Public Health Sciences Division, received a V Foundation Translational Grant providing $800,000 over 4 years. Cheung will study new ways to target triple-negative breast cancer cells, so named because they lack estrogen receptors, progesterone receptors and sufficient levels of HER2 protein, which promote the growth of cancer cells. Research into new potential targets is crucial because the drugs used to treat hormone-receptor or HER2-positive breast cancers are not as effective for those with TNBC.
Malfunctioning cell machinery leads to new cancer targets
Haffner’s research focuses on the science of epigenetics, the changes that occur on top of strands of genetic material that can either enhance or repress the expression of specific genes. “Epi” is a prefix originating in the Greek language that means “over” or “above.”
In the epigenetic process known as DNA methylation, molecules called methyl groups are attached to portions of DNA, which hold the genetic code for producing cell proteins. With 20,000 genes located on the human DNA molecule, these epigenetic additions lead to a myriad of specific changes and form the basis of gene expression and cell identity.
“One thing that is pretty striking to me, and has been so since my training, both in the lab and then also as a pathologist, is that a key differentiating feature between cancer cells and benign cells is how the epigenome is structured,” Haffner said.
During the COVID-19 pandemic when laboratory research slowed down, Haffner found himself with large amounts of time to read through existing research. He revisited literature on the epigenetics of cancer cells, especially DNA hypomethylation (a loss of expected methylation of DNA in specific cells), which had been observed in many different types of solid tumor cancer cells as early as the 1980s.
“Arguably the first description of an epigenetic change in cancer was that a lot of solid tumors lost DNA methylation,” Haffner said.
However, studies that looked further into how cancer cells with DNA hypomethylation functioned were lacking. That led to the project for which the V Foundation awarded Haffner an All-Star Grant, “AKTing on DNA hypomethylation.” The All-Star Grant is awarded to previous V Foundation grant recipients who are nominated by their institutions as the “best of the best” in their fields. Haffner previously received a V Scholar grant in 2021 for a project studying prostate cancer cells at the single-cell level.
AKT is a protein that acts as a growth signal in hypomethylated cancer cells. When AKT is blocked, cells turn to another signaling system known as Polycomb Repressive Complex 2 (PRC2) to survive.
Haffner’s team previously demonstrated that when both AKT and PRC2 are blocked at the same time, cancer cells can be killed much more effectively. The goal of Haffner’s new study is to develop a clinical trial using AKT and PRC2 blockers to treat cancer patients whose solid tumors show signs of DNA hypomethylation.
“If successful, this approach could lead to a more personalized treatment for patients with cancer,” Haffner wrote in his grant application.
Targeting the machinery of the tumor cell itself is a promising new approach to attacking solid tumors. With a number of FDA-approved AKT and PRC2 blockers already available, Haffner believes that a breakthrough for DNA-hypomethylated solid cancers could be on the horizon.
He credits his frequent collaborator, Michael Schweizer, MD, a Fred Hutch medical oncologist, with helping him to develop these ideas. Haffner also cites the critical work of Pallabi Mustafi, PhD, a postdoctoral researcher in his lab, who undertook the fundamental studies that demonstrated the vulnerability that hypomethylated cancer cells have to AKT inhibitors already in use for certain types of cancer. Those early findings and collaborative conversations set the stage for Haffner’s current project.
You will receive a monthly newsletter from us about our innovative research and compassionate care as well as updates on events and other helpful tools and tips.
You may unsubscribe at any time.
“No one [else] had associated [AKT inhibitors] with DNA methylation at that point,” Haffner explained. The AKT inhibitors create “striking effects at very low doses of the drug, [and] only in the tumors that have low global methylation. That was our first insight that these tumors have a vulnerability that we can immediately go after with drugs that are [already] available that are reasonably well tolerated.”
Further experiments showed that blocking AKT forces cancer cells to depend on a second pathway, known as PRC2, to stay alive. Since drugs targeting PRC2 are already being tested in patients, Haffner and his team were able to combine the two approaches. Together, the drugs were more effective than either treatment alone, offering a promising new strategy for treating advanced prostate cancer.
Haffner hopes that the first clinical trial, supported by the V Foundation grant, will demonstrate that using both drugs together to treat hypomethylated solid tumors will lead not only to new treatments for solid tumors, but fewer side effects as well.
“We saw significantly increased effect [with both drugs]” while reducing the dosages of each drug, Haffner said. “So, not only do they work better together, but now you can spare a patient some of the side effects. The anticipation is that this combination of therapies will be very well tolerated.”
Tricking triple-negative breast cancer cells into changing their identity
Triple-negative breast cancer (TNBC) occurs in up to 20% of all breast cancer patients, and can be highly aggressive, dividing more quickly and exhibiting increased resistance to standard cancer treatments such as chemotherapy. TNBC is particularly difficult to treat because of the absence of obvious markers that could be targeted with existing hormone-specific cancer drugs. Without receptors for estrogen or progesterone inside the cell, or significant amounts of the protein HER-2 on the cell surface, TNBC cells are harder to treat than other breast cancer subtypes. It’s a predicament that keeps Cheung, the recipient of a V Foundation Translational Grant, up at night.
“I've been trying to understand how cancer cells, particularly breast cancer cells, metastasize,” Cheung said. "Metastatic cancer cells have the aggression dial turned way up, making them spread rapidly, seed different sites, and resist therapies. What if you could turn the aggression dial way down?"
This is Cheung’s second grant from the V Foundation. He previously received a 2017 V Scholar Grant for a project studying mechanisms of cancer metastasis. For his current project, Cheung is looking at molecular clues in cancers without obvious drug targets to take advantage of their cellular machinery to make them less aggressive.
While breast cancers identified by the presence or absence of hormonal receptors are known as “clinical subtypes,” these cancers can also be described based on their molecular or morphological characteristics, such as their shapes and how they act under certain conditions. These so-called “molecular subtypes” include one type of tumor commonly seen in TNBC: the presence of cancer cells that resemble basal epithelial cells, a type of cell normally seen in the epidermis, the top layer of human skin.
The idea that a triple-negative breast cancer cell could resemble an epidermal cell suggested to Cheung that perhaps these cells could be coaxed into acting like them as well. That could provide a new avenue for the treatment of TNBC, by tricking these cancer cells into acting like cells that routinely die instead of multiplying uncontrollably.
Cheung’s project, “Irreversible differentiation of triple-negative breast cancer via targeted UPS inhibition,” targets a class of proteins known as the ubiquitin-proteasome system (UPS). The UPS system degrades old proteins in cells and recycles their remnants to build new proteins inside the cell. It is a key mechanism in cellular biology that allows cells to survive and multiply.
Cheung believes that UPS inhibitors, drugs with FDA approval that are in common use for multiple myeloma, could be used to identify and kill basal-like tumor cells in TNBC. He plans to use his grant to conduct critical experiments that will help in the design of a clinical trial for patients whose TNBC has already been successfully treated, in the hopes that the basal-like tumor cells that could seed a relapse could be eradicated before causing a recurrence of the cancer.
He credits breast cancer oncologist Sara Hurvitz, MD, senior vice president and director of the Clinical Research Division, and myeloma oncology expert Andrew Portuguese, MD, an assistant professor in the Clinical Research Division, for helping him conceptualize how these drugs can be repurposed for therapeutic use in TNBC. Hurvitz holds the Smith Family Endowed Chair in Women’s Health.
“Once [TNBC cells] start acting like skin cells, they can't spread or grow,” Cheung wrote in his grant application. “This approach could stop TNBC before it comes back and becomes life-threatening.”
The implications for patients are substantial. Cheung notes that TNBC has the highest rate of relapse of all types of breast cancer within five years after the initial diagnosis. By the time a relapse is detected, many millions of TNBC cells will have already seeded the recurrence.
Cheung’s project will determine whether UPS inhibitors can drive TNBC cells to differentiate into basal-like cells, and whether these cells normally digest and degrade the proteins known as transcription factors that drive cells to differentiate into basal skin cells. From there, he plans to determine how to identify TNBC patients that could benefit from UPS inhibitor-based therapy to prevent a relapse of their cancer.
The planned clinical trial aims to treat TNBC patients in remission with UPS inhibitors in the hopes that these drugs will degrade basal-like cells that could otherwise proliferate and create new tumors. Cheung will work in collaboration with cancer epidemiologist Christopher Li, MD, PhD, senior vice president and director of the Public Health Sciences Division. Li holds the Helen G. Edson Endowed Chair for Breast Cancer Research.
“UPS inhibition has never been studied in the context of micrometastasis eradication [the eradication of small amounts of cancer cells before a diagnosable relapse occurs],” Cheung said. His hope is that by tricking basal-like cells into acting like skin cells that normally die off instead of proliferating uncontrollably, these studies will lead to a new class of treatments for cancer that look not at surface markers for drugs but cellular shapes and activities that can be disrupted.
The V Foundation for Cancer Research, based in Raleigh, North Carolina, has provided over $458 million to support cancer research of all types, with a focus on high-risk, high-reward research strategies. The foundation began with initial funding provided by the sports broadcaster ESPN. Acclaimed college basketball coach Jimmy Valvano (the “V” of the foundation’s name), diagnosed with metastatic adenocarcinoma in 1992, announced the foundation in a speech at the inaugural ESPY Awards for excellence in sports in 1993. Fred Hutch scientists have since received over $8 million in research funding from the foundation.
