Fat Rats Show Why Breast Cancer May Be More Aggressive in Patients with Obesity

Women with obesity are more likely to get breast cancer, and a number of studies have provided a reasonable explanation why: after menopause, fat tissue manufactures estrogen, and the estrogen then promotes tumor growth. But why, then, do women with obesity continue to have more aggressive tumors even after anti-estrogen treatment? Once the tumor’s source of estrogen is removed, obesity should have no effect on prognosis, but it does.

A University of Colorado Cancer Center study published in the journal Hormones & Cancer offers a possible explanation: In an animal model of obesity and breast cancer (affectionately referred to as the “fat rat”), tumor cells in obese animals, but not lean animals, had especially sensitive androgen receptors, allowing these cells to magnify growth signals from the hormone testosterone. Similar to the way in which many breast cancers drive their growth with estrogen receptors, these tumors in obese rats drove their growth with androgen receptors.

“Our original goal was to make a model of obesity and breast cancer that would reflect the condition in women.  At first, we were disappointed to discover that rats don’t make much estrogen in fat tissue like humans do. But we then realized that this aspect of the model gave us an excellent opportunity to study cancer progression after anti-estrogen treatment. Because fat cells in these rats don’t make estrogen, they are like human breast cancer patients treated to remove estrogen.  This allowed us to ask what is responsible for obesity-associated tumor progression in conditions of low estrogen availability,” says Elizabeth Wellberg, PhD, the paper’s first author, who works with Steven Anderson, PhD and Paul MacLean, PhD. Dr. Anderson is the vice chair for research at CU Cancer Center and James C. Todd Professor of Experimental Pathology in the CU School of Medicine. Dr. MacLean is a professor in the Division of Endocrinology, Metabolism, & Diabetes, also in the CU SOM.  Together, these investigators and their team have identified an important role for obesity in changing how breast tumors respond to hormones.

About 40 percent of American women have obesity; about 75 percent of breast cancers are estrogen-receptor positive, most of which will go on to be treated with anti-estrogen therapies. This combination means that thousands of women every year could benefit from treatments aimed at the aspects of obesity that promote breast cancer in low- or non-estrogen environments.

Androgen receptors and their hormone partner, testosterone, have long been known as drivers of prostate cancer and work at CU Cancer Center and elsewhere is implicating androgen as a driver in many breast cancers. When Wellberg and colleagues treated their obese rats with the anti-androgen drug enzalutamide, existing tumors shrank and new tumors failed to form. But this brought up another question: If overactive androgen receptors create poor prognosis in obese breast cancer patients, what is creating these overactive androgen receptors? It wasn’t that they were simply responding to more testosterone – it was that these receptors had been somehow tuned to be more sensitive to existing levels of testosterone.

“When you talk about what’s different between lean and obese individuals there are a lot of things – resistance to insulin, high sugar, and an elevated inflammatory response, what we call chronic low-grade inflammation, to name a few. In a lot of ways, you can walk through these differences looking for what may be causing this androgen receptor sensitivity,” says Anderson.

The group had previously shown that a component of inflammation, namely levels of a cytokine known as interleukin 6 (IL-6), is higher in the circulation of obese compared to lean rats. In the current paper, the group shows that administering IL-6 to breast cancer cells amplifies the activity of androgen receptors. In all, the storyline of this paper suggests the following:

  • Obesity leads to inflammation
  • Inflammation is associated with higher levels of IL-6
  • IL-6 sensitizes androgen receptors
  • Sensitized androgen receptors amplify growth signals that drive breast cancer even in an environment of low estrogen availability.

The current paper and others in this line of study lay the groundwork for considering obesity as a variable in the clinic.

“Down the line, we can imagine a day in which the BMI or metabolic state of breast cancer patients would be considered when choosing a treatment. These patients may benefit significantly from a more personalized therapeutic strategy, based on what obesity is doing to the tumor environment,” Wellberg says.

New Driver, Target in Advanced Mucosal Melanoma

Not all melanomas are created equal. While most melanomas appear on the skin as the result of sun exposure, a small subset of melanomas arise spontaneously from mucosal tissues. And while targeted treatments and immunotherapies have dramatically improved the prognosis for many patients with sun-associated melanomas, these treatments are ineffective in the mucosal form of the disease. A University of Colorado Cancer Center study published today in the journal Melanoma Research uses the unique resource of over 600 melanoma samples collected at the university to demonstrate, for the first time, novel mutations involved in mucosal melanoma, paving the way for therapies to treat this overlooked subtype.

“The treatment for melanoma has gotten pretty good in the past five years. But this is a different disease and the treatments that work in sun-caused melanoma don’t work in non-sun melanoma,” says William A. Robinson, MD, investigator at the CU Cancer Center and the Rella and Monroe Rifkin Endowed Chair of Medical Oncology at the CU School of Medicine. Robinson founded the melanoma tissue bank at CU, which has grown into a major national resource for scientists studying the disease.

The study compared whole-exome sequencing data from 19 patient samples of mucosal melanoma to 135 samples of sun-exposed melanoma. Importantly, mutations in the BRAF gene that are seen in more than half of advanced melanomas were absent in mucosal melanoma, explaining the ineffectiveness of BRAF-targeted treatments like vemurafenib. Instead, 32 percent of mucosal melanomas showed co-mutation of the genes KIT and NF1. Also, the paper reports mutations in the gene SF3B1 present in 37 percent of mucosal melanoma samples.

“We have seen SF3B1 mutation in chronic lymphocytic leukemia and in myeloid dysplastic disorders, and now we show its importance in mucosal melanoma,” says Aik Choon Tan, PhD, investigator at the CU Cancer Center and associate professor of Bioinformatics at the CU School of Medicine.

Because any sample of cancer cells is likely to contain thousands of mutations, advanced analytic tools are needed to distinguish harmless “passenger” mutations from the dangerous mutations driving the disease. For this purpose, the researchers used the computational tool IMPACT, developed in the Tan lab, to sort functional from missense mutations and to cross-reference candidate mutations with those previously reported in other cancer types.

“For the first time, this process demonstrates the functional role of SF3B1 in mucosal melanoma,” Robinson says.

The mechanics of SF3B1 are complex and only partially understood. Basically, the gene makes a molecule involved in preparing other genes for expression, helping to distinguish between regions of genes that should be manufactured and those that are silent genetic filler. Technically, SF3B1 sorts “exons” from “introns” – helping to cut and splice genetic code into the streamlined version that forms the plan for a protein. Unfortunately, if SF3B1 is mutated, this cutting and pasting can go awry in ways that introduce unintended bits of introns along with the intended bits of exons into the blueprint.

“Most often when material from introns is improperly included with exons, the result is nonsense proteins that go on to quickly degrade, meaning that cancer may use this strategy to downregulate the production of certain anti-cancer proteins,” Tan says. “On the other hand, an SF3B1 mutation could result in changes to the protein that are helpful to cancer cells, meaning that mucosal melanoma may be using this strategy to upregulate the production of proteins that can drive its growth.”

No matter if SF3B1 is nixing good proteins or boosting bad ones, the current project shows that stopping its action could benefit patients with mucosal melanoma. In fact, the researchers point out that phase 1 clinical trials are already underway for compounds targeting this gene in other cancers, meaning that the time needed to apply a similar strategy to mucosal melanoma could be dramatically shorter than if they had to start from scratch.

The group plans to continue exploring the mechanics of SF3B1 while also pushing forward with the preclinical work needed to form the rational basis for targeting this gene in patients with advanced mucosal melanoma.

Tucatinib (ONT-380) Progressing in Pivotal Trial Against HER2+ Breast Cancer

Phase 1 clinical trial data published this week in the journal Clinical Cancer Research show early promise of the investigational anti-cancer agent tucatinib (formerly ONT-380) against HER2+ breast cancer. The 50 women treated had progressed despite a median 5 previous treatment regimens. Twenty-seven percent of these heavily pretreated patients saw clinical benefit from the drug, with at least “stable disease” at 24 or more weeks after the start of treatment. These data led to two subsequent Phase Ib studies, resulting in tucatinib earning FDA fast-track status and the expansion of this study once meant only to demonstrate drug safety into the “pivotal” trial that will determine approval.

“Usually we expect the results of a phase 1 clinical trial to give us data that we can use to guide the results of future treatments. This is a great case in which, for many of these patients, the results were immediate. There are women who are alive today because of this drug,” says Virginia Borges, MD, MMSc, director of the Breast Cancer Research Program and Young Women’s Breast Cancer Translational Program at the University of Colorado Cancer Center. Borges has been a major driver of the drug’s development from its invention at Array Biopharm in Boulder, CO and now through clinical trials of the drug, which is licensed to Cascadian Therapeutics of Seattle, WA.

Tucatinib is a small molecule inhibitor of the HER2 growth factor receptor. The drug works by targeting the HER2 “tyrosine kinase” – a link in the chain of communication that allows HER2 receptors to signal the growth of the cell. The fact that it is a small molecule means the drug is able to pass through the blood-brain barrier to act against brain metastases of the disease. HER2+ breast cancer is more likely to affect younger women and also more likely than other breast cancers to metastasize specifically to the brain.

Working with Borges’s Young Women’s Breast Cancer Translational Program at CU Cancer Center, young investigator Elena Shagisultanova, MD, PhD, recently earned a $1.4m competitive ASPIRE grant from Pfizer, Inc., to conduct a clinical trial exploring the use of tucatinib against so-called “triple positive” breast cancer – those cancers driven by both estrogen and progesterone receptors and the HER2/neu oncogene.

“When both [estrogen and HER2] are positive, they counteract the therapy aimed at one or the other, playing off each other like kids splitting parents,” Borges says. More specifically, when both avenues are present, the crosstalk leads to tumors being resistant to treatment, as either avenue can allow the cancer to survive therapy. Previous trials concurrently targeting estrogen and HER2 have been, according to Borges, “lackluster,” resulting in no changes to the standard of care.

The forthcoming trial lead by Shagisultanova will be a multi-center clinical trial with CU Cancer Center as the lead site, testing the combination of three drugs – tucatinib plus the anti-estrogen receptor drug letrozole and the cell cycle inhibitor palbociclib – against breast cancers positive for both HER2 and estrogen receptors.
“Tucatinib could be a substantially practice-changing drug,” Borges says, meaning that in addition to the drug’s current investigations as a third-, fourth-, or more-than-fifth-line treatment, she envisions its use sooner in the arc of breast cancer treatment and with far more patients.

“I think this drug has an extremely high likelihood of being approved for women with HER2+ breast cancer for use after previous treatments,” Borges says. “And it’s going to be an especially important drug due to its ability to control brain metastases. The opportunity to study it as a front-line drug for recurrent triple positive breast cancer could even someday help us prevent or delay these brain metastases.”

Because the drug is taken in pill form and has a very favorable side effect profile, Borges points out that it is relatively patient-friendly, allowing women to avoid treatments in infusion centers and also many of the side-effects associated with chemotherapies.