When you think about University of Colorado Cancer Center, you might picture our new treatments offered through partners like UCHealth, Children’s Hospital Colorado, and the CSU Flint Animal Cancer Center. But it takes years or even decades of basic and translational science to make these treatments possible. For May’s National Cancer Research Month, we looked back at our science from May 2019 to May 2020 to see what promising new ideas may drive tomorrow’s treatments. Here are condensed versions of a few of our highlights. Check out the full articles to learn more!
Since 1974, scientists have thought that cells decide whether or not to replicate based on a snapshot of their surroundings. Now a study by the lab of Sabrina Spencer, PhD, CU Cancer Center investigator and assistant professor in the CU Boulder Department Biochemistry, together with lead author Mingwei Min, PhD, postdoctoral fellow in Dr. Spencer’s lab, shows it’s more like a movie.
A study by CU Cancer Center researchers working at Children’s Hospital Colorado shows pediatric oncology clinical trial enrollment may be down, from 40-70 percent seen in studies completed in the 1990s, to 20-25 percent in the early 2000s, to 19.9 percent in the current study. “One reason trial enrollment may be decreasing is that good treatments have been developed for some of the most common childhood cancers, shifting the focus and resources toward opening trials for higher risk, but often more rare cancers,” says Kelly Faulk, MD, CU Cancer Center investigator and pediatric oncologist at Children’s Hospital Colorado.
The use of PET-CT imaging gives doctors the best possible picture of non-small cell lung cancer (NSCLC), and this accurate imaging helps to match patients with the best treatments. Unfortunately, not every NSCLC patient gets the recommended PET-CT imaging. Now a University of Colorado Cancer Center study published in the Journal of the National Cancer Institute shows an important predictor of PET-CT use: African American patients were only about half as likely as non-Hispanic whites to receive this important imaging; Hispanics received this imaging about 70 percent as frequently as non-Hispanic whites. “Now that we know more about this problem, we must find ways to address it,” says Rustain Morgan, MD, CU Cancer Center investigator and assistant professor in the CU School of Medicine Department of Radiology.
A small study of 48 patients with locally advanced rectal cancer receiving neoadjuvant chemotherapy, found that patients receiving lower-than-recommended doses in fact saw their tumors shrink more than patients receiving the full dose. “This is a small, single-institution study, but it certainly gives us pause,” says Ashley E. Glode, PharmD, assistant professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences, and the study’s first author. “Why would patients take more chemotherapy and have more side effects, when less chemotherapy seems equally or even more beneficial?”
A massive research effort over more than a quarter century has tried to make personalized blood stem cells for use in treating leukemias, among many other uses. In this effort, hematopoietic stem cells (HSCs) don’t seem to cause cancer like induced pluripotent stem cells(iPSCs). Unfortunately, researchers have been unable to create HSCs that can take hold and grow in the body. Now a University of Colorado Cancer Center study identifies a possible new way to make HSCs. And, ironically, a possible way to do this lies in magnifying a gene that causes a form of childhood leukemia. “My lab was working on a gene called MLL that, when accidentally fused together with another gene, causes childhood leukemia,” says Patricia Ernst, PhD, CU Cancer Center investigator and Professor in the CU School of Medicine Departments of Pediatrics. What Ernst’s studies show is that doubling the amount of the regular MLL protein in pluripotent stem cells, can push these cells to produce more blood cells. The finding may help to develop usable HSCs that could regrow a leukemia patient’s blood system after the chemotherapy and radiation used to kill the cancer.
The red, tube-shaped flowers of the firecracker bush ( Bouvardia ternifolia) provide the chemical bouvardin, which the lab of University of Colorado Cancer Center and CU Boulder researcher, Tin Tin Su, PhD, and others have shown to slow a cancer’s ability to make proteins that tell cancer cells to grow and spread. Now a paper based on nearly half a decade of work, published in the journal Cancer Research, shows that the molecule SVC112, based on bouvardin and synthesized by Su’s Colorado-based pharmaceutical startup, SuviCa, Inc. acts specifically against head and neck cancer stem cells (CSCs), resulting in better tumor control with less toxicity to healthy cells than existing, FDA-approved protein synthesis inhibitors. The group hopes these promising preclinical results will lay the groundwork for human clinical trials of SVC112 in head and neck cancer patients.
Pooled analysis of three phase 1 and 2 clinical trials published online ahead of print in the journal Lancet Oncology show that the drug entrectinib is effective and well-tolerated against advanced ROS1 and NTRK fusion-positive non-small cell lung cancers (NSCLC). Based on the early promise of these trials, in August 2019 the U.S. Food and Drug Administration granted entrectinib accelerated approval for the treatment of metastatic ROS1+ NSCLC and for advanced tumors across cancer types defined by NTRK fusion. “For a drug to get simultaneous approval for use against two different targets is somewhat unique. I don’t know of this ever happening before,” says Robert C. Doebele, MD, PhD, director of the University of Colorado Cancer Center Thoracic Oncology Research Initiative, senior author on the ROS1 study, and first author on the NTRK study.
Phase III clinical trial results reported today in the New England Journal of Medicine and presented concurrently at the San Antonio Breast Cancer Symposium (SABCS) 2019 show the combination of the investigational drug tucatinib with standard of care treatment including the drugs trastuzumab and capecitabine nearly tripled one-year progression-free survival (33 percent vs. 12 percent), and nearly doubled the two-year overall survivor (45 percent vs. 27 percent) in women with HER2+ metastatic breast cancer. The international, multi-center trial, named HER2CLIMB ( NCT02614794), builds on early development and clinical trials involving the University of Colorado Cancer Center. “Tucatinib is one of the most promising new drugs that we have brought forward for women with stage IV HER2-positive breast cancer, especially those with brain metastases,” says Virginia Borges, MD, MMSc, director of the Breast Cancer Research Program and Young Women’s Breast Cancer Translational Program at CU Cancer Center.
In melanoma, myeloid-derived suppressor cells (MDSCs) are bad – the more MDSCs, the poorer a patient’s prognosis. But how do MDSCs expand and how do they accumulate near melanoma tissue? A University of Colorado Cancer Center study published in the journal Frontiers in Oncology hints at an answer. Chemicals in the body called interleukins regulate the immune system and the current study shows that the interleukin called IL-6 may help to grow MDSCs, while another called IL-8 may recruit MDSCs toward tumor tissue. “This is building on some work we had done showing that melanoma patients with higher MDSC concentrations had poorer outcomes. But we didn’t know if it was chicken or egg – were MDSCs driving melanoma or was the melanoma inducing more MDSCs? This takes it to the next level, showing a functional role for IL-6 and IL-8 in driving melanoma outcomes,” says Martin McCarter, MD, CU Cancer Center investigator and surgical oncologist at the UCHealth University of Colorado Hospital.
When prostate cancer spreads, it most often spreads to bone. And while the 5-year survival rate for prostate cancer that has not spread is nearly 100 percent, once the disease reaches bone, the 5-year survival rate is only 29 percent. Now a University of Colorado Cancer Center study published in the Journal for Immunotherapy of Cancer suggests a new approach, or, possibly two new approaches against these bone metastases: While targeted therapies and anti-cancer immunotherapies have not been especially successful against primary prostate cancers, the study suggests that both these approaches may be effective against the bone metastases that grow from primary prostate cancers. “We developed a test that can directly measure immunotherapy and pathway targets in bone metastases,” says Philip Owens, PhD.. “This is significant because we could potentially use this as a test to determine which of the many immunotherapies could be best for an individual patient, one at time, and truly provide a personalized therapy.”
With improved treatments, especially the use of anti-cancer immunotherapies, more than two-thirds of all patients diagnosed with diffuse large B-cell lymphoma (DLBCL) will survive. However, after treatment, patients are at a small but real risk of developing a new cancer, called a second primary cancer. Now a Colorado study of long term DLBCL survivors shows, for the first time, that the stage at which DLBCL is originally diagnosed impacts the types of second cancers that may form after treatment. “This is a first step toward identifying tools in survivorship clinics to better surveil survivors. It benefits patients because we may be able to better identify risk,” says Manali Kamdar, MD, investigator at the University of Colorado Cancer Center and Clinical Director of Lymphoma Services at UCHealth University of Colorado Hospital.
Prostate cancers that lose the gene MAP3K7 are genetically unstable and especially dangerous. But this genetic instability comes at a cost – a CU Cancer Center study shows that these MAP3K7-negative cells gain genetic instability at the cost of a dismal capacity for DNA repair. In other words, their instability makes them delicate. “We’re excited,” says James Costello, PhD. “There’s still a lot more work to do, but this approach could really change the way we think about targeting prostate cancer.”
The TERT gene is the third most commonly mutated gene in cancer. When cancer over activates TERT, it manufactures more of the enzyme “telomerase,” which rebuilds protective chromosome endcaps called telomeres faster than they are degraded, making cells immortal. Unfortunately, despite a massive effort by research and pharmaceutical communities, there is no silver bullet that successfully turns off over-activated TERT in human cancer patients. Now a study by Nobel Laureate, Thomas Cech, PhD, University of Colorado Cancer Center investigator and Director of the Biofrontiers Institute at University of Colorado Boulder, offers an intriguing new way to target TERT over-activation. “Our hypothesis is that there’s a special mechanism for transporting TERT mRNA into the cytoplasm that is really slow or inefficient, and that this is another level of regulation that most genes don’t need. But TERT needs this special step in regulating the transport of mRNA – and if that’s the case, maybe that could be a new target for interfering with this transport step. Maybe we could attack TERT in cancer cells by keeping mRNA trapped in the nucleus,” Cech says.
Breast cancer patients and women undergoing cancer-preventive breast surgeries may consider combining these procedures with hysterectomy and/or ovarian removal. However, a University of Colorado Cancer Center study published in Breast Journal argues against this combined approach: Patients undergoing coordinated breast and gynecologic procedures had a significantly longer length of hospital stay, and higher complication, readmission, and reoperation rates compared with patients who underwent single site surgery. “Patients have the impression, ‘I just want to have one surgery and have everything done.’ But complication rates are higher with that approach. Outside of rare cases, we recommend separating breast and reconstructive surgery from gynecologic surgery,” says Sarah Tevis, MD, CU Cancer Center investigator and breast surgeon at UCHealth University of Colorado Hospital.
When it comes to using radiation against lung cancer, it seems like more should be better. So why did a large phase 3 clinical trial find exactly the opposite – that stage III non-small cell lung cancer patients treated with higher doses of radiation actually had shorter overall survival than patients treated with lower-dose radiation? A new study offers an interesting answer: Blame it on the immune system. That’s because radiation used in the lung doesn’t stay in the lung. This radiation hits blood passing through lung and heart as well. And compromising the immune components of blood removes an important ally in the body’s fight against cancer. “Our hypothesis is that higher doses of radiation to the immune system is contributing to worse survival in those patients,” says Sameer K. Nath, MD, University of Colorado Cancer Center investigator and assistant professor in the CU School of Medicine Department of Radiation Oncology.
A study by University of Colorado Cancer Center and Colorado State University Flint Animal Cancer Center sequences 33 canine cancer cell lines to identify “human” genetic changes that could be driving these canine cancers, possibly helping veterinary oncologists use more human medicines to cure cancer in dogs. “We’re taking what we know from human cancers and applying it in canine cancers to help move the canine cancer treatment forward faster,” says Dawn L. Duval, PhD, investigator at CU Cancer Center and assistant professor in the CSU College of Veterinary Medicine and Biomedical Sciences.
Results of University of Colorado Cancer Center phase 1b study presented at the American Society for Clinical Oncology (ASCO) Annual Meeting 2019 offers an attractive alternative to the chemotherapy that is often used to treat breast cancers driven by hormone receptors and HER2: the three-drug cocktail of targeted treatments – tucatinib, palbociclib and letrozole – was overall well-tolerated and showed preliminary evidence of promising anti-cancer activity. Results support the continued development of the combination in an ongoing phase 2 clinical trial. “I see this as a promising chemotherapy-free combination for patients who have been without good options, especially for those whose disease has spread to the brain,” says Elena Shagisultanova, MD, PhD, investigator at CU Cancer Center and the trial’s principal investigator.
University of Colorado Cancer Center led clinical trial data show that a predictive tool called COXEN may show which bladder cancer patients will respond to pre-surgical chemotherapy, a step towards allowing doctors to offer such chemotherapy to patients likely to respond, while moving more efficiently to other treatment options with patients unlikely to benefit. “The idea is that for any individual tumor, its gene expression could tell us whether the cancer will respond to a certain kind of chemotherapy,” says Thomas Flaig, MD, Vice Chancellor for Research on the Anschutz Medical Campus. “This is an important clinical application of a concept developed by investigators based in Colorado, which may have implications in predicting the response to chemotherapies across many cancer types.”
A University of Colorado Cancer Center study presented at the American Society for Clinical Oncology (ASCO) Annual Meeting 2019 shows that while 73 percent of surveyed oncology providers believe that medical marijuana provides benefits for cancer patients, only 46 percent are comfortable recommending it. “I think in some cases we’re missing out on providing a useful tool. Providers think it has benefit, but aren’t comfortable recommending it,” says Ashley E. Glode, PharmD, assistant professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences, and the study’s first author.