On Tuesday, November 5, University of Colorado Cancer Center members met to present cutting-edge research taking place in labs and clinics across CU Cancer Center consortium partners, including CU Anschutz, CU Boulder, CSU Flint Animal Cancer Center, the UCHealth system, Children’s Hospital Colorado, Denver Health, and the Denver V.A. Medical System. “As Director of CU Cancer Center, I have come to realize and experience the energy and collegiality of our cancer center, the vast amount of hard work and progress we’ve made over the past years,” said Richard Schulick, MD, MBA, CU Cancer Center Director, opening the event.
First to speak was Colorado Lieutenant Governor, Dianne Primavera.
“If you had told me 31 years ago in September that I would be standing here as Lieutenant Governor, I would have said that was cruel,” Primavera said. That’s because 31 years ago, Primavera was diagnosed with breast cancer and given five years to live. “I lost my job, my health insurance, my marriage crumbled under the pressure. How was I going to put food on the table and keep a roof over my daughters’ heads? And they had to cope with the fact their mother was dying.” Her search for a medical oncologist would treat her with hope instead of resignation brought her to Dr. William Robinson at CU Cancer Center.
“He said, ‘Oh hell, Diane, you’re healthier than 95 percent of the doctors in this hospital. Come with me and we’ll make you well — and he did,” Primavera says, mentioning that because on the day of the retreat she was technically acting governor, she would like to make a state mandate that Dr. Robinson can’t retire.
First on the scientific program was Craig Jordan, PhD, Nancy Carroll Allen Chair and Chief of the CU School of Medicine Division of Hematology. Basically, Dr. Jordan described an Achille’s heel of cancer stem cells, the cells that commonly survive chemotherapy and other treatments to restart many forms of the disease. This Achille’s heel is the dependence of cancer stem cells on a special form of energy. Most cells burn glucose; cancer stem cells burn amino acids. Now, based on these findings, doctors are using the drug venetoclax to block the uptake of amino acids by cancer stem cells, leading to a 91 percent response rate in patients with acute myeloid leukemia, a form of cancer that previously had a dismal prognosis. Additional clinical trials are testing combinations of venetoclax with other chemotherapies and targeted therapies in other cancer populations.
“It’s providing significant clinical benefit for patients with a horrible disease,” Jordan said.
Next, Diana Cittely, PhD, CU Cancer Center investigator and assistant professor in CU School of Medicine Department of Pathology described the role of estrogen in promoting brain metastasis in estrogen-negative breast cancers.
The problem is that breast cancers that don’t depend on estrogen, and especially those known as triple-negative breast cancers (that also don’t depend on HER2 or progesterone), are difficult to treat and especially likely to metastasize to the brain. What drives this dangerous behavior? Cittelly’s work shows that while estrogen doesn’t directly affect triple-negative breast cancer cells, it can affect surrounding brain cells in ways that promote cancer cell migration and invasiveness. Importantly, she suggests ways to stop the activity of estrogen in the brain that fertilizes triple-negative breast cancer metastasis.
“The cancer cells aren’t responsive to estrogen, but estrogen influences the microenvironment. We found that astrocytes – one of the main components of the microenvironment in the brain – are estrogen-responsive. When they are stimulated with estrogen, they produce chemokines, growth factors, and other things that promote brain metastasis,” Cittelly said. Specifically, she suggests that estrogen may magnify the effect on other known cancer-promoting pathways, including EGFR and TrkB.
After a coffee break, York Miller, MD, described the best time to treat lung cancer: Before it fully forms. The period of pulmonary “premalignancy” is a bit like the more well-known period in which a colon polyp has not yet become cancer. Left to their own devices, these precancerous conditions often progress into cancer; Miller described the development of interventions to prevent this progression.
“As a pulmonary doctor, I’m interested in prevention and early detection of lung cancer,” Miller said. Specifically, he described deficiencies in normal processes of lung tissue repair that lead to an environment in which premalignant cells can grow (as in tissues affected by smoking or COPD).
“By keeping track of people over time, we have been able to see the progression from premalignant conditions to lung cancer,” Miller said, showing slides of patient lung tissue taken over decades, showing this progression. The progression often starts with a condition known as squamous dysplasia, frequently resulting from smoking. Treatments like iloprost cna improve dysplasia and reduce lung cancer risk. Miller’s current work is focused on immunotherapies to reverse squamous dysplasia and achieve similar cancer-prevention effects.
Then Sunnie Kim, MD, assistant professor at CU School of Medicine and gastroenterologist at UCHealth University of Colorado Hospital (who arrived from the NIH only three months ago and so instead of a faculty photo is illustrated here with her Twitter profile image), spoke about her work with DNA damage and repair in cancers of the esophagus. Basically, the body seeks to repair DNA damage or kill cells with this damage, while cancer cells depend on DNA damage to create the differences that make them cancerous. This means that many cancers break these DNA repair pathways, often through the action of a gene called PARP.
“We’ve been thinking about adding DNA damaging agent with a checkpoint inhibitor — or the thought is doing a little lead-in with a DNA damaging agent to cause immune presentation, followed by a checkpoint inhibitor,” Kim says. Based on these ideas, Kim is running a clinical trial combining the PARP inhibitor, naraparib, with anti-PD-1 immunotherapy against esophageal cancer.
Sabrina Spencer, PhD, assistant professor in the CU Boulder Department of Chemistry and Biochemistry, followed with a presentation describing how melanoma cells escape therapy long enough to develop the genetic changes that let them further resist therapy.
“If all the cells are initially drug sensitive, how do these cells survive the drug long enough to develop resistance mutations?” she asked.
To answer this questions, Spencer watched individual melanoma cells that depend on the gene BRAF evade anti-BRAF therapy. What she found is that even within three days of treatment, melanoma cells find a way to activate a survival pathway known as MEK – not with mutations, but with a more flexible and temporary way to allow these cancer cells to continue survival signaling. In fact, the FDA recently approved combination treatment in BRAF+ melanoma, using the drug dabrafenib against BRAF and another drug, trametinib, against MEK to delay this escape. Still, Spencer shows that 3 percent of BRAF+ melanoma cells continue to survive this combination treatment, and the question remained how? Spencer’s recent work with single cell RNA sequencing identified suspicious activation of 34 genes in these “escapee” cells that may drive their escape, half of which are targeted by the single gene ATF4 and 7 of which predict poor patient prognosis (making ATF4 or other genes in the ATF4 pathway possible targets to further reduce the escape of BRAF+ melanoma cells).
During lunch, attendees voted for grad student, postdoc and early-career scientist posters, including those describing new treatments for canine bladder cancer, emotional distress in head & neck cancer patients, chronic pain in young cancer survivors, autophagy inhibition in brain tumors, the role of macrophages in creating resistance to targeted treatments, and the role of ancient viruses in shaping the body’s response to cancer.
After lunch, Traci Lyons, PhD, spoke about factors that increase breast cancer risk in women undergoing postpartum mammary gland involution, the process by which the lactating mammary gland returns to its pre-pregnant state. Her previous work has implicated the molecule SEMA7A in the recurrence and metastasis of breast cancers across age and subtype. Now Lyons’ work shows that SEMA7A may drive cancer through suppressing immune system action against tumors. Findings may influence the design of drugs targeting SEMA7A directly, or clinical trials attempting to resensitize the immune system against breast cancers expressing SEMA7A.
Breelyn Wilky, MD, described a push to personalize the use of anti-cancer immunotherapies in the treatment of sarcoma. Basically, despite the fact that the genetics of sarcomas vary considerably, a one-size-fits-all approach to immunotherapy has been used to treat them. Wilky’s work suggests that subtypes of sarcoma may respond better when immunotherapy is combined with other targeted therapies, for example perhaps those against DGFRα/KIT, β-Catenin/APC/NOTCH, IDH-1/2 mutations, MDM2 amplifications, EZH2/INI1 expression loss, ALK fusion, or ASPSCR1-TFE3 fusion.
The retreat’s final scientific speaker was Evelinn Borrayo, PhD, CU Cancer Center Associate Director for Community Outreach and Engagement, who spoke about interventions to improve mental health outcomes among lung cancer and head & neck cancer survivors and caregivers. Interestingly, it is specifically because patients with these cancers are surviving longer that researchers are starting to turn their attention to issues of survivorship and quality of life. During November’s Family Caregiver Awareness Month, it seemed especially fitting that the CU Cancer Center retreat’s final scientific speaker included the experience of caregivers in her presentation.
