Using a genetic signature to overcome chemotherapy-resistant lung cancer

Patients with non-small cell lung cancer (NSCLC) often respond to standard chemotherapy, only to develop drug resistance later, and with fatal consequences. But what if doctors could identify those at greatest risk of relapse and provide a therapy to overcome or avoid it?

Researchers at UT Southwestern Medical Center believe they have an answer: a 35-gene signature that identifies tumor cells most likely to develop resistance to treatment. The study, published today in Cell Reports, points to a new pharmacologic approach to target chemo-resistant lung cancer and even prevent development of such resistance in the first place.

Cancer relapse after chemotherapy poses a major obstacle to treating lung cancer, and resistance to chemotherapy is a big cause of that treatment failure,” said study co-author Dr. John Minna, a Professor and Director of in the Hamon Center for Therapeutic Oncology Research at UT Southwestern. “These findings provide new insights into why resistance develops and how to overcome it.

Dr. Minna, with additional appointments in Pharmacology and Internal Medicine, also holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology. Investigators studied mouse and cellular models of NSCLC, a type of lung cancer that the American Cancer Society estimates accounts for 85 percent of all lung cancer cases in the United States.

Previous studies have shown that up to 70 percent of those cancers develop resistance to standard therapy, such as the platinum-taxane two-drug combo that is often given,” said study senior author Dr. Elisabeth D. Martinez, Assistant Professor of Pharmacology and in the Hamon Center. Both she and Dr. Minna are also members of UTSW’s Harold C. Simmons Comprehensive Cancer Center.

Using long-term on/off drug cycles, lead author and former postdoctoral researcher Dr. Maithili Dalvi developed a series of cellular models of progressive tumor resistance to standard chemotherapy that ranged from very sensitive to highly insensitive. Next, the researchers identified genes commonly altered during the development of resistance across multiple cell line and mouse models and identified a 35-gene signature that indicated a higher genetic likelihood of chemotherapy resistance.

It’s like a fingerprint for resistance,” Dr. Martinez said, adding that it was predictive in both cells and mouse models.

Next, they compared this resistance biomarker using genetic profiles from human tumors in their National Cancer Institute (NCI) lung cancer Specialized Programs of Research Excellence (SPORE) database at UT MD Anderson Cancer Center in Houston. The database contained information on patient outcomes and those who had been treated with the two-drug chemotherapy. The genetic fingerprint for resistance correlated with cancer relapse in NSCLC patients in the database, she said.

Researchers discovered that as cancer cells developed greater resistance to chemotherapy, they progressively made higher amounts of enzymes called JumonjiC lysine demethylases. Dr. Martinez said these enzymes facilitate resistance by changing the expression of – or turning on and off – genes.
Cancer cells use these enzymes to change, or reprogram, gene expression in order to survive the toxic stress of the chemotherapy. By changing the expression of genes, the tumor cells can adapt and survive the toxins,” she said.

Investigators then tested two potential drugs, both JumonjiC inhibitors. One of them, JIB-04, was found by UT Southwestern researchers in the Martinez lab during a small-molecule screen conducted at the National Center for Advancing Translational Sciences’ Chemical Genomics Center in Bethesda, Maryland.

I believe this is the first report of NSCLC tumors taking advantage of multiple JumonjiC enzymes to reprogram gene expression in order to survive chemotoxic stress. In addition, and this is the most fascinating part: Dr. Dalvi found that greater chemotherapy resistance defines a new susceptibility to the JumonjiC inhibitors,” she said. “The cancer cells develop a new Achilles’ heel that we can hit.”

Because the chemo-resistant cancer cells are dependent on JumonjiC enzymes for survival, inhibiting those enzymes returns cancer cells to mortality and vulnerability to cell death, she explained.
We think these JumonjiC inhibitors have the potential to be used either to treat tumors once they become resistant to standard therapies, or to prevent resistance altogether,” she said. “In our experiments these inhibitors appear to be much more potent in killing cancer cells than normal cells.”

Later, researchers tested whether the Jumonji inhibitors JIB-04 or GSK-J4 prevented chemotherapy resistance. This strategy succeeded in cell cultures and partially prevented resistance in animal models, Dr. Martinez said.

Dalvi et al. Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors.Cell Reports, 2017;19:1669–1684 [Article]

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Race, hospital, insurance status all factors in how lung cancer is treated

African Americans, Hispanics, and those who receive care at a community hospital are all significantly less likely than other patients to receive treatment for early stage non-small cell lung cancer, according to a report in the Journal of Thoracic Oncology.

We found significant disparities for treatment of a curable cancer based on race, insurance status, and whether or not treatment was at an academic or community hospital,” said Dr. Matthew Koshy, a physician in the department of radiation oncology at the University of Illinois at Chicago College of Medicine, and lead author of the study. “Reducing these disparities could lead to significant improvements in survival for many people with inoperable early stage lung cancer.

The study is the largest to date looking at treatment received by patients with stage I non-small cell lung cancer, an early stage of lung cancer that has not spread to the lymph nodes and is characterized by a small nodules in the lung tissue. Treatment during this early stage offers the best chance for long-term survival.

Surgery to remove cancerous nodules in the lungs is the standard treatment for patients with stage I NSCLC. But many patients cannot undergo surgery, due to complicating medical conditions such as poor lung function or heart disease.

For those patients, radiation therapy has been the standard treatment, but outcomes are much poorer than for surgical treatment. Many patients deemed inoperable are only monitored, because the benefits of conventional radiation are regarded as minimal.

Over the last 10 years, a new radiation technology called stereotactic body radiotherapy, or SBRT, has replaced conventional radiation as the standard treatment for inoperable stage I NSCLC. It delivers much higher doses of radiation, requires fewer treatments, is better tolerated, and has survival outcomes comparable to surgery.

Koshy and his colleagues wanted to know if any factors predicted whether a patient was more likely to be observed, treated with conventional radiation, or treated with SBRT — and if there were any disparities in the use of those treatments.

They looked at data from nearly 40,000 patients with inoperable stage I NSCLC added to the National Cancer Database between 2003 and 2011. The hospital-based cancer registry collects information on patient demographics, insurance status, diagnosis, treatment and outcome.

The analysis showed that African Americans were 40 percent less likely, and Hispanics 60 percent less likely, to be treated with radiation — either conventional radiation or SBRT. Of patients who did receive radiation, African Americans and those with no insurance were less likely to receive SBRT.

Patients were two-and-a-half times more likely to receive SBRT in academic hospitals than in community hospitals, and seven times more likely to receive SBRT at a high-volume medical center than at a low-volume center.

The researchers found that in 2011, 46 percent of patients receiving care in community care centers were only observed, compared to 21 percent of patients at academic medical centers. Sixty-eight percent of patients at academic medical centers received SBRT compared to 25 percent of patients at community hospitals.

Koshy suggests that all patients with early stage inoperable lung cancer be evaluated by a radiation oncologist, and that more radiation oncologists trained in SBRT are needed. Better access to facilities that offer SBRT could help reduce the disparities the study uncovered, he said.

Koshy et al. Disparities in Treatment of Patients with Inoperable Stage I Non-Small Cell Lung Cancer: A Population-Based Analysis. J Thorac Oncol. 2014; EPub Ahead of Print. doi: 10.1097/JTO.0000000000000418 [Abstract]

Increased overall survival for advanced stage non-small cell lung cancer patients is associated with availability of less toxic chemotherapy

A 10-year population-based study shows that increased availability of better systemic chemo- and targeted-therapies for patients with advanced non-small cell lung cancer (NSCLC) coincides with increased usage of these therapies. This in turn leads to a significant increase in overall survival.

Researchers from the British Columbia Cancer Agency, Vancouver, Canada, performed a retrospective chart review of all patients referred to the agency with advanced stage (IIIB or IV) lung cancer and grouped the patients into 4 one-year time frame cohorts; one termed “baseline” and three other groups that each started 6-months after a new second-line agent (docetaxel, erlotinib and pemetrexed) was made commercially available and put into practice. In British Columbia, Canada, the implementation of the second-line agents docetaxel, erlotinib and pemetrexed occurred in December 2000, October 2005 and June 2007, respectively. Cohort 1 (January to December 1998) with 555 patients was the baseline and cohort 2 (May 2001-April 2002) had 613 patients, cohort 3 (March 2006-February 2007) had 688 patients and Cohort 4 (November 2007-Ocotober 2008) had 750 patients.

The results published in the August Issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer, show that the usage of second-line therapy increased significantly over time. At baseline only 21% of the patients received second-line therapy but in Cohorts 2 and 3 this increased to 27% and 37% respectively, and by Cohort 4 more than half, 55%, received second-line therapy. The most common agent in Cohort 1 was docetaxel (48%) but by Cohort 4 erlotinib (EGFR TKIs) and pemetrexed were used 50% and 26% of the time. The research also found that the proportion of patients who received at least first-line systemic chemotherapy also increased over the four time points from 16% in Cohort 1 to 23%, 34% and 33% for Cohorts 2-4, respectively.

The median overall survival of the patients who did not receive any chemotherapy did not change over the four time points; 3.9, 4.0, 3.1 and 3.2 months (p=0.136), however for those that did receive chemotherapy survival increased significantly, 9.4. 9.8 11.0 and 11.8 months (p=0.023). Examination of the entire population showed that the median overall survival of those not receiving chemotherapy was 3.51 months, whereas those receiving first-line therapy was 7.9 months and for those receiving second-line or beyond therapy the survival was 17 months (p<0.001).

The authors note that “The benefits of chemotherapy and specifically second-line treatment on patient outcomes are substantial, even in a widely mixed population of patients, which confirms the advances seen in clinical trial populations over the past decade“. Likewise, “As the options for treatment of NSCLC expand we anticipate that the outlook for lung cancer will continue to improve.”

Ho et al., (2014). Less Toxic Chemotherapy Improves Uptake of All Lines of Chemotherapy in Advanced Non–Small-Cell Lung Cancer: A 10-Year Retrospective Population-Based Review. J. Thoracic Oncol., 9: 1180-1186, doi: 10.1097/JTO.0000000000000225 [Abstract]

Hormone therapy linked to better survival after lung cancer diagnosis in women

Survival among people with lung cancer has been better for women than men, and the findings of a recent study indicate that female hormones may be a factor in this difference. The combination of estrogen plus progesterone and the use of long-term hormone therapy were associated with the most significant improvements in survival.

The study was designed to explore the influence of several reproductive and hormonal factors on overall survival of women with non-small cell lung cancer (NSCLC). After adjusting for stage of disease at diagnosis, treatment type (surgery or radiation), smoking status, age, race, and education level, the only factor studied that predicted survival after a diagnosis of NSCLC was use of hormone therapy.

Among the 485 women, the median survival time was 80 months for women receiving hormone therapy and 37.5 months for women not receiving hormone therapy. Combined estrogen and progesterone was associated with a slightly higher median survival time (87.0 months) than estrogen alone (83.0 months). The findings of the study are published in the March issue of the International Association for the Study of Lung Cancer’s journal, the Journal of Thoracic Oncology (JTO).

The use of hormone therapy for 11 years or more was associated with significantly improved survival, and this finding remained significant among women who took either estrogen alone or estrogen plus progesterone and among women who had never smoked or were smokers.

What has emerged from this study and other published findings is a complex relationship between hormone use and lung cancer outcomes, with variation in results based on years of use,” says lead author Ann G. Schwartz, PhD, MPH, of Karmanos Cancer Institute, Detroit, MI, and an IASLC member.

Studies on the effect of hormone use on lung cancer survival have been limited, and the results have been inconsistent. Because of this, additional research is needed to evaluate the significance of long-term use of hormone therapy on outcomes in lung cancer, with better characterization of tumors in terms of expression of estrogen and progesterone receptors.

Dr. Schwartz adds, “There is more to learn about survival differences between men and women; hormone use may contribute to those differences. The largest impact on lung cancer outcomes will come from successful early detection and treatment.”

Katcoff et al., (2014). Survival in women with NSCLC: The role of reproductive history and hormone use.J.Thorac.Oncol.9:355-361 [Abstract]