2-Drug Combination May Boost Immunotherapy Responses in Lung Cancer Patients

Johns Hopkins Kimmel Cancer Center researchers and colleagues have identified a novel drug combination therapy that could prime nonsmall cell lung cancers to respond better to immunotherapy. These so-called epigenetic therapy drugs, used together, achieved robust anti-tumor responses in human cancer cell lines and mice.

During the study, published Nov. 30, 2017, in the journal Cell, a team of researchers led by graduate student Michael Topper; research associate Michelle Vaz, Ph.D.; and senior author Stephen B. Baylin, M.D., combined a demethylating drug called 5-azacytidine that chemically reignites some cancer suppressor genes’ ability to operate, with one of three histone deacetylase inhibitor drugs (HDACis). The HDACis work against proteins called histone deacetylases that are involved in processes, such as cell copying and division, and can contribute to cancer development. The combination therapy triggered a chemical cascade that increased the attraction of immune cells to fight tumors and diminished the work of the cancer gene MYC. Based on these findings, investigators have launched a clinical trial of the combination therapy in patients with advanced, nonsmall cell lung cancer.

The development of therapeutic approaches for patients with lung cancer has been a critical medical need, says Baylin, the Virginia and Daniel K. Ludwig Professor of Cancer Research at the Kimmel Cancer Center. While immune checkpoint therapy has been “a tremendous step forward, less than half of patients with lung cancer have benefited to date,” he says.

“In our study, the two-drug epigenetic therapy combination worked exceedingly well, even before putting in the immune checkpoint inhibitors,” Baylin says. “In animal models of lung cancer, the two agents either prevented cancer from emerging or blunted the effects of more aggressive cancers. In both scenarios, a large component of the results involved an increase in immune recognition of the tumors.”

In a series of experiments, researchers studied the combination of 5-azacytidine with the HDACis entinostat, mocetinostat or givinostat in human cancer cell lines and in mouse models of nonsmall cell lung cancers. The treatments were found to alter the tumor microenvironment. In cancer cell lines, 5-azacytidine worked against the cancer gene MYC, causing down regulation of the entire MYC signaling program. Adding the HDACis further depleted MYC, and together the drugs subsequently caused actions that prevented cancer cell proliferation, simultaneously attracted more immune system T cells to the area of the tumor and activated these cells for tumor recognition.

In mouse models, the strongest response was observed when using 5-azacytidine plus givinostat. In one mouse model with a mutant form of nonsmall cell lung cancer, this drug combination given for three months yielded prevention of benign, precursor tumors from becoming cancers and caused 60 percent reduction of overall area of benign tumor appearance in the lungs. By contrast, a group of mice with the same form of lung cancer that were given a mock treatment universally developed large, cancerous lesions in the lungs.

In a second model of mice with established, aggressive, nonsmall cell lung cancer, treatment with an alternating schedule of 5-azacytidine with givinostat and of 5-azacytidine with mocetinostat not only reduced the growth of established, rapidly growing primary tumors but also dramatically reduced metastatic occurrence.

Baylin and colleagues at Memorial Sloan Kettering Cancer Center in New York and Fox Chase Cancer Center in Philadelphia have started a phase I/Ib clinical trial to evaluate if giving mocetinostat with a 5-azacytidinelike drug called guadecitabine can boost immune checkpoint therapy responses in patients with advanced, nonsmall cell lung cancers. The trial is part of the Van Andel Research Institute–Stand Up To Cancer Epigenetics Dream Team and is funded by Merck through the Stand Up To Cancer  (SU2C) Catalyst program, an initiative led by SU2C to bring innovative cancer treatments to patients quickly. Matthew Hellmann, M.D., an author on the paper, will lead this trial at Memorial Sloan Kettering, and Jarushka Naidoo, M.B.B.Ch., assistant professor of oncology, will lead at Johns Hopkins. For more information, click here.

Deadly Lung Cancers Are Driven by Multiple Genetic Changes

Blood-Based Cancer Tests Reveal Complex Genomic Landscape of Non-Small Cell Lung Cancers

A new UC San Francisco–led study challenges the dogma in oncology that most cancers are caused by one dominant “driver” mutation that can be treated in isolation with a single targeted drug. Instead, the new research finds one of the world’s most deadly forms of lung cancer is driven by changes in multiple different genes, which appear to work together to drive cancer progression and to allow tumors to evade targeted therapy.

These findings — published online on November 6, 2017 in Nature Genetics — strongly suggest that new first-line combination therapies are needed that can treat the full array of mutations contributing to a patient’s cancer and prevent drug resistance from arising.

“Currently we treat patients as if different oncogene mutations are mutually exclusive. If you have an EGFR mutation we treat you with one class of drugs, and if you have a KRAS mutation we pick a different class of drugs. Now we see such mutations regularly coexist, and so we need to adapt our approach to treatment,” said Trever Bivona, MD, PhD, a UCSF Medical Center oncologist, associate professor in hematology and oncology, and member of the Helen Diller Family Comprehensive Cancer Center at UCSF.

Lung cancer is by far the leading cause of cancer death worldwide. Efforts to identify the genetic mutations that drive the disease have led to targeted treatments that improve life expectancy for many patients, but these drugs produce temporary remission at best — sooner or later, cancers inevitably develop drug resistance and return, deadlier than ever.

The new UCSF-led study — which analyzed tumor DNA from more than 2,000 patients in collaboration with Redwood City–based Guardant Health — is the first to extensively profile the genetic landscape of advanced-stage non–small cell (NSC) lung cancer, the most common form of the disease.

“The field has been so focused on treating the ‘driver’ mutation controlling a tumor’s growth that many assumed that drug-resistance had to evolve from new mutations in that same oncogene. Now we see that there are many different genetic routes a tumor can take to develop resistance to treatment,” said Bivona, who is also co-director of a new UCSF-Stanford Cancer Drug Resistance and Sensitivity Center funded by the National Cancer Institute. “This could also explain why many tumors are already drug-resistant when treatment is first applied.”

A blood test can predict early lung cancer prognosis

Cancer cells obtained from a blood test may be able to predict how early-stage lung cancer patients will fare, a team from the University of Michigan has shown.

This information could be used to determine which patients are most likely to benefit from additional therapies to head off the spread of the cancer to other areas of the body.

With a new single cell analysis service in U-M’s Comprehensive Cancer Center, the researchers are making the necessary technology more widely available in the university system. They hope these “liquid biopsies” will be offered to patients within the next five years.

Circulating tumor cells, representing only about one in a billion cells in the bloodstream, are largely untapped sources of information about tumors, but new methods are bringing their diagnostic value ever closer to patient care.

Sunitha Nagrath, U-M professor of chemical engineering who designs devices that can capture these rare cells, led a team including oncologists and surgeons to explore how cancer cells escape tumors and travel through the body in the bloodstream. This is how metastases, or satellite tumors elsewhere in the body, are thought to form.

“The tumors were constantly shedding cells even when they were small–that’s one thing we learned,” Nagrath said. “Although we define the tumors as early stage, already they are disseminating cells in the body.”

Early-stage lung cancer patients, whose tumors may only measure a few millimeters in diameter, are typically treated with surgical removal of the tumor, but the study results suggest that this may not be enough. A handful of patients had tumors that were shedding hundreds or thousands of tumor cells into the lung.

“Even though you removed the tumor, you left behind these hundreds and hundreds of cells,” Nagrath said. “If you know this patient walking out of the clinic is going to relapse after less than a year because of these cells, why don’t we treat them now?”

With a relatively small sample of 36 patients, the team can’t definitively say that an actively shedding tumor will lead to metastasis within a year, but Nagrath is exploring the predictive power of cancer cells drawn from the blood. In particular, the study showed that clusters of two or more tumor cells indicated shorter survival times. Six of the nine patients whose cancer returned during the two to 26 months of follow-up had circulating tumor cells appearing in clusters.

“Ultimately, this method will help us look for and find potential markers for either metastatic spread or cancer detection,” said Rishindra Reddy, U-M associate professor of surgery who coordinated the blood samples and designed the study with Nagrath and Nithya Ramnath, an associate professor of medical oncology at the U-M Medical School.

Gangs of aggressive cells

Genetic analysis confirmed that clusters showed higher expression of aggressive traits. They were better at moving, evading the immune system, recruiting blood cells to help them and resisting treatments. In other words, clustered tumor cells were better suited to spreading cancer to distant locations.

“These are drivers of tumor progression and resistance, and they are more important to target with therapy,” Nagrath said.

To gather the data underpinning these findings, the team took blood samples before, during and after tumor removal surgery. At each stage, surgeons collected blood from a vein in the patient’s arm, far from the tumor. Early in surgery, before disturbing the tumor, the surgeon also drew blood from the lung vein that drained from the tumor, where tumor cells are expected to be more concentrated.

And they were–as Vasudha Murlidhar, then a doctoral student in the Nagrath lab, showed by analyzing all the samples using a microfluidic chip of her own design. While tumor cells from the arm had a median count of around 1.3 per 3 milliliters, it was 7.5 per 3 ml of blood from the lung. Among the patients whose lung blood samples revealed hundreds or even thousands of tumor cells, the numbers fell sharply by the time the cells reached the vein in the arm.

It couldn’t be explained by mere dilution. The researchers hypothesize that the larger clusters are getting stuck in capillaries–potentially the start of a new tumor–or that many of these cells can’t survive in the bloodstream.

Toward monitoring cancer with blood tests

Nagrath is impatient to see liquid biopsy begin to benefit patients at U-M. Already, this study demonstrates that capturing cancer cells from the bloodstream can indicate which patients are most in need of a second treatment, such as chemotherapy, to go after the cells that have already dispersed in the body. It could also help doctors choose drugs that will be better at exploiting the weaknesses of these aggressive cells.

Nagrath is advancing the technology at U-M by co-directing a new service arm within the Cancer Center. The new Single Cell Analysis Core will isolate cancer cells from blood using many different microfluidic chips, developed by Nagrath’s group and others.

Evan Keller, a professor of urology in the Medical School, will lead the cell analysis techniques. This effort will primarily help cancer researchers better understand the disease for now, but Nagrath is hopeful that it won’t be long before liquid biopsies are part of routine patient care at Michigan Medicine.

“With a simple blood draw, we can tell the dynamic state of the disease during the treatment and after the treatment, monitoring it closely. If something has to show up on a CT scan, it may already be too late,” Nagrath said.

The study is titled “Poor prognosis indicated by venous circulating tumor cell clusters in early stage lung cancers” and will appear in Cancer Research.

The microfluidic chips for isolating cancer cells were produced at the Lurie Nanofabrication Facility at U-M. Captured cells were analyzed with the help of the Microscopy and Image Analysis Laboratory and the Cancer Center’s DNA Sequencing Core at U-M. This study was funded by the National Institutes of Health Director’s New Innovator Award, the U-M Lefkofsky Scholarship and the U-M Rackham International Student Fellowship.

Vasudha is now a postdoctoral scholar in biomedical engineering at the University of California, Davis.

Research suggests possible new treatment for EGFR-positive lung cancer

Findings from a phase III clinical trial point to a potential new treatment for patients newly diagnosed with advanced, epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). Compared to the EGFR inhibitor gefitinib (Iressa), one of the standard targeted medicines for this disease, second-generation EGFR inhibitor dacomitinib delayed cancer growth by a median of 5.5 months more.

The study was featured in a press briefing and presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.

Each year, about 140,000 people worldwide (15,000 in the United States alone) are diagnosed with EGFR-positive NSCLC. EGFR-positive cancers have genetic changes that lead to an overactive EGFR protein, which fuels the growth of cancer cells. EGFR tyrosine kinase inhibitors (TKI) are the standard treatment for people with newly diagnosed EGFR-positive NSCLC. This study is the first phase III head-to-head comparison of two EGFR TKIs.

“We changed the treatment paradigm for EGFR-positive lung cancer a few years ago when targeted therapy replaced chemotherapy,” said lead study author Tony Mok, MD, a professor and chair of the Department of Clinical Oncology at the Chinese University of Hong Kong. “This study shows that dacomitinib may be an even more effective treatment for these patients. However, patients should be aware of the need to deal with potential side effects when making treatment decisions.”

“It’s been nearly 15 years since EGFR-targeted therapies were introduced, helping extend survival for thousands of patients in the time since. The second generation of these therapies is more effective, but can also cause greater side effects, so patients and their doctors will need to weigh the risks and benefits,” said ASCO Expert John Heymach, MD, PhD.

Due to its chemical properties, dacomitinib blocks EGFR more effectively than first-generation inhibitors, such as gefinitib and erlotinib, and this explains its ability to keep tumor growth in check longer. On the other hand, this also leads to stronger suppression of the normal EGFRs in healthy tissues, causing more side effects such as skin rash, acne, and diarrhea.

About the Study

In this phase III clinical trial, researchers randomly assigned 452 patients newly diagnosed with IIIB or IV, EGFR-positive NSCLC to receive dacomitinib or gefitinib. The patients were enrolled in Asia and Europe.

Key Findings

Patients who received dacomitinib had a 41% lower chance of cancer progression or death than those who received gefitinib. The progression-free survival was 14.7 months with dacomitinib, compared to 9.2 months with gefitinib. Longer follow up is needed to assess the median overall survival.

The most common severe (grade 3) side effects of dacomitinib were acne (in 14% of patients) and diarrhea (in 8% of patients). The dose of daconitinib was lowered in about 60% of patients due to side effects. Liver enzyme abnormalities were the most common severe (grade 3) side effect of gefitinib (in 8% of patients).

“Dacomitinib is a more potent, second-generation EGFR inhibitor that shares the issue of increased side effects in the skin and gastrointestinal tract, like afatinib (Gilotrif). In spite of this, the activity seen in this study should allow for consideration of this effective therapy in this patient population,” said Dr. Mok. Another second-generation EGFR inhibitor, afatinib, is already FDA approved as an initial treatment for EGFR-positive NSCLC. Dacomitinib is not yet approved for any indication.

Thorough Genotyping and Repurposed Drugs Key to Treating Small-Cell Lung Cancer, says Cancer Expert

Small cell lung cancer (SCLC) is an aggressive disease characterized by quick growth and spread. While there has been a gradual decrease in incidence of SCLC in recent years, likely reflecting the decreased prevalence of tobacco use, little progress has been made in treating SCLC due to its complex pathogenesis.

The majority of patients, including those with limited-stage disease and those who initially respond to chemo- and radiation- therapy (two traditional pillars of cancer therapy), become resistant to treatment resulting in a very small percentage (approximately 6%) who survive 5 years after being diagnosed.

Smoking is the main risk factor for SCLC, with only 2-3% of patients categorized as never-smokers.

Identifying Therapeutic Targets in Small-Cell Lung Cancer

From the molecular point of view, SCLC is characterized by a multitude of alterations, owing to the fact that cells are exposed to a myriad of carcinogens contained in cigarette smoke, which bind and mutate DNA. These alterations affect numerous genes and pathways, but among these there are few obvious therapeutic targets. This means that the driver genes responsible for most SCLC development and progression have yet to be identified with any certainty.

However, new high-throughput technologies, which allow comprehensive gene profiling, have revealed promising findings. For example, 20% of SCLC patient tumors bear alterations in the MYC gene family. This discovery has helped to identify a subset of patients sensitive to an oncogenic kinase downstream in the MYC pathway, allowing for better designed, biomarker-driven clinical trials for these, often repurposed, therapeutic agents.

Similarly, PARP1 and Notch have been found overexpressed in SCLC. In order to target PARP1, an enzyme which, when it malfunctions, leads to replication of damaged DNA, researchers are currently evaluating the efficacy of PARP inhibitors for treatment of SCLC. And, to investigate targeting of the Notch signaling pathway, which influences the cellular life-cycle, the FDA is in the process of approving Tarextumab, a selective Notch inhibitor, in the treatment of SCLC.

Another issue with SCLC tumors is that they are mostly characterized by the loss of two crucial oncosuppressor genes, named RB, RB2\p130 i and TP53, which are less actionable pharmaceutically because it is much more difficult to restore a loss of function rather than block an oncogenic gain of function. Although challenging, researchers are nonetheless trying to develop strategies in this direction.

Repurposing Existing Drugs

Also important to the progress of SCLC therapies, more effective drug identification and testing, through the use of powerful mouse models of the human disease, put researchers in a good position to tackle this cancer type and attempt better defined targeted approaches.

Recent immunotherapy approaches have emerged as a significant new pillar in cancer therapy and are being assessed in numerous clinical trials for a multitude of tumors, including SCLC. In particular, two new agents, nivolumab and ipilimumab, have recently been developed to treat other forms of cancer, such as unresectable or metastatic malignant melanoma, advanced non-small-cell lung cancer (NSCLC), and advanced renal-cell carcinoma. These agents have also been tested for applications in SCLC. Nivolumab and ipilimumab are constituted by monoclonal antibodies functioning through direct inhibition of CTLA4 and PD1, respectively, which are key negative regulators of the antitumoral immune function. Bristol-Myers Squibb (BMS) was able to obtain the National Comprehensive Cancer Network indication for use of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. The indication was achieved upon the publication on Lancet Oncology by Scott Antonia and colleagues, who reported the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab, achieving antitumour activity with durable responses and manageable safety profiles in previously treated SCLC patients, enrolled in the CheckMate-032 clinical trial.

Data was also presented at the World Lung Cancer Congress on the immunotherapy drug pembrolizumab, another therapeutic antibody against PD1, already approved for other diseases, which showed good efficacy.

One additional drug in this category is rovalptizumab teserine, a first-in-class antibody-drug conjugate comprised of a humanized monoclonal antibody against DLL3 and a toxin. DLL3 is a Notch ligand found to be expressed on 80% of SCLC. There is a 3rd line trial which is biomarker driven, meaning that they test for DLL3 expression and patients are eligible if they have “high” DLL3.

 

Scientists Find Possible Achilles Heel of Treatment Resistant Cancers

Scientists identify two signaling proteins in cancer cells that make them resistant to chemotherapy, and show that blocking the proteins along with chemotherapy eliminate human leukemia in mouse models.

Reporting results March 20 in Nature Medicine, researchers at Cincinnati Children’s Hospital Medical Center suggest that blocking the signaling proteins c-Fos and Dusp1 as part of combination therapy might cure several types of kinase-driven, treatment-resistant leukemia and solid tumor cancers.

These include acute myeloid leukemia (AML) fueled by the gene FLT3, lung cancers fueled by genes EGFR and PDGFR, HER2-driven breast cancers, and BCR-ABL-fueled chronic myeloid leukemia (CML), according to Mohammad Azam, PhD, lead investigator and a member of the Division of Experimental Hematology and Cancer Biology.

“We think that within the next five years our data will change the way people think about cancer development and targeted therapy,” Azam says. “This study identifies a potential Achilles heel of kinase-driven cancers and what we propose is intended to be curative, not just treatment.”

The weak spot is a common point of passage in cells (a signaling node) that appears to be required to generate cancer cells in both leukemia and solid tumors. The node is formed by the signaling proteins c-Fos and Dusp1, according to study authors. The researchers identified c-Fos and Dusp1 by conducting global gene expression analysis of mouse leukemia cells and human chronic myeloid leukemia (CML) cells donated by patients.

CML is a blood cancer driven by an enzyme called tyrosine kinase, which is formed by the fusion gene BCR-ABL. This fusion gene is the product of translocated chromosomes involving genes BCR (chromosome 22) and ABL (chromosome 9). Analysis of human CML cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive chemotherapy resistant cells.

Cancer sleeper cells

Cancer cells often become addicted to the mutated gene that causes them, such as BCR-ABL in kinase-driven chronic myeloid leukemia. Most chemotherapies work by blocking molecular pathways affected by the gene to shut down the disease process. In the case of CML, a chemotherapy called imatinib is used to block tyrosine kinase, which initially stops the disease. Unfortunately the therapeutic benefit is temporary and the leukemia comes back.

Azam and colleagues show in their CML models that signaling from tyrosine kinase – and growth factor proteins that support cell expansion (like interleukins IL3, IL6, etc.) – converge to dramatically elevate c-Fos and Dusp1 levels in the cancer cells.

Working together these molecules maintain the survival of cancer stem cells and minimal residual disease. The dormant cells wait around under the radar screen to rekindle the disease by acquiring additional genetic mutations after initially effective chemotherapy.

Azam says Dusp1 and c-Fos support the survival of cancer stem cells by increasing the toxic threshold needed to kill them. This means conventional imatinib chemotherapy will not eliminate the residual disease stem cells. Doctors can’t just increase the dose of chemotherapy because it doesn’t target the Dusp1 and c-Fos proteins that regulate toxic threshold.

Targeting c-Fos and Dusp1

After identifying c-Fos and Dusp1, the authors tested different treatment combinations on mouse models of CML, human CML cells, and mice transplanted with human leukemia cells. They also tested treatments on B-cell acute lymphoblastic leukemia (B-ALL).

The treatment combinations included: 1) solo therapy with just the tyrosine kinase inhibitor, imatinib; 2) solo treatment with just inhibitors of c-Fos and Dusp1; 3) treatment with all three combined – imatinib along with molecular inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression but the leukemia relapsed with the continued presence of residual disease cells. Treatment with c-Fos and Dusp1 inhibitors alone significantly slowed CML progression and prolonged survival in a majority of mice but wasn’t curative. Treatment for one month with c-Fos/Dusp1 inhibitors and imatinib cured 90 percent of mice with CML, with no signs of residual disease cells.

Azam and his colleagues also point to an interesting finding involving solo treatment with just the deletion of c-Fos and Dusp1. This eliminated expression of the signaling proteins and was sufficient to block B-ALL development, eradicating the disease in mouse models.

Next steps

The authors stress that because the study was conducted in laboratory mouse models, additional research is needed before the therapeutic strategy can be tested in clinical trials.
They are following up the current study by testing c-Fos and Dusp1as treatment targets for different kinase-fueled cancers, including certain types of lung cancer, breast cancers and acute forms of leukemia.

Yale Study Identifies New Way To Suppress Lung Tumors

Lung cancer cell growth depends on certain proteins that require the addition of sugar molecule chains to become active. Scientists have long thought that the addition of these sugar chains is like an on or off switch, and that blocking their addition would be harmful. Now a Yale-led research team has identified a new blocking mechanism that acts more like a dimmer switch and potently inhibits lung tumor cell growth.

Senior author Joseph Contessa and his co-authors screened hundreds of thousands of chemical compounds to uncover a new inhibitor that reduces the addition of sugar chains without harming non-tumor cells. Based on this finding, the research team plans to test the compound in preclinical studies as a potential new strategy for treating lung cancer — the leading cause of cancer death nationwide.

Optimal Management For NSCLC Patients With Brain Metastases

A Yale Cancer Center team completed a multi-institutional analysis of treatment options for patients with newly diagnosed EGFR-mutant non-small cell lung cancer (NSCLC) with brain metastases to determine the best option for treatment. Stereotactic radiosurgery, in combination with targeted therapy using EGFR tyrosine kinase inhibitors, resulted in the longest survival and best outcomes for patients. The findings were presented September 26 at the American Society for Therapeutic Radiology and Oncology (ASTRO) meeting in Boston.

This study analyzed three current options by reviewing outcomes of 351 patients from six institutions with EGFR-mutant NSCLC who were treated with either stereotactic radiosurgery in conjunction with targeted therapy (100), whole brain radiotherapy in conjunction with targeted therapy (120), or targeted therapy alone followed by stereotactic radiosurgery or whole brain radiotherapy if salvage was required (131).

The multi-institutional analysis demonstrated that the use of targeted therapy alone with deferral of radiotherapy resulted in inferior overall survival. Stereotactic radiosurgery in conjunction with targeted therapy resulted in the longest overall survival for patients.

“Patients with advanced NSCLC that has newly spread to their brain have many treatment options today,” said Veronica Chiang, MD, senior author on the study and an Associate Professor of Neurosurgery and of Therapeutic Radiology at Yale School of Medicine. “Physicians need to feel confident that we know the best option and this study helps us to identify that. A randomized trial will be our next step.”

Bristol-Myers Squibb Drug Fails Lung-Cancer Study

A blockbuster cancer treatment failed in a key study as the drug’s maker, Bristol-Myers Squibb, attempts to extend its usage for lung cancer patients.

Shares of the New York company plunged 16 percent Friday, its biggest one-day drop in 14 years. Shares of rival Merck & Co., which makes a rival cancer drug, spiked 10 percent to reach an 18-year high.

Bristol’s drug, Opdivo, and Merck’s drug Keytruda are immunotherapies, which bolster the immune system so that patients can better fight cancer. Both drugs are already approved to treat melanoma and lung cancer, but only after chemotherapy.

In June, Merck reported positive results from a key study focusing on Keytruda as a lone treatment for lung cancer. The negative results from Bristol appear to put Merck in the lead for treating cancer patients without resorting to chemotherapy and its drastic side effects.

The latest late-stage study for Opdivo involved 541 patients who had received no prior treatment for lung cancer.

“We remain committed to improving patient outcomes through our comprehensive development program,” said Bristol-Myers CEO Dr. Giovanni Caforio.

-Associated Press

Researchers inhibit tumor growth in new subtype of lung cancer

Lung cancer is the most common cause of cancer deaths, accounting for about a third of all tumor-related deaths. Adenocarcinomas, a non-small cell lung cancer (NSCLC), account for about 40 percent of cancer diagnoses, but few treatments are available for the disease.

A team of investigators led by Elena Levantini, PhD, a research associate in Hematology-Oncology at Beth Israel Deaconess Medical Center (BIDMC), instructor of medicine at Harvard Medical School and a member of the Harvard Stem Cell Institute, have identified a subtype of human adenocarcinoma. The research could help determine which individuals are at greatest risk of developing lung tumors that may be amenable to a new therapy to inhibit their progression. The results – done in collaboration with the Cancer Science Institute at the National University of Singapore (CSI NUS) – were published today in the journal Science Translational Medicine.

“Advances in lung cancer therapy require a greater understanding of the molecular origins of this deadly disease,” said last corresponding author Levantini, who is also a researcher at the Institute of Biomedical Technologies at the Italian National Research Council (ITB-CNR). “Understanding the differences among lung cancers also could lead to innovations in treatment strategies and allow us to overcome drug-resistance, relapse and disease progression.”

Levantini and colleagues previously showed that NSCLC tumor cells frequently express too little or none of a transcription factor called C/EBPα, a protein that regulates gene expression and cell proliferation in lung tissues. It’s also known to play a role in a form of leukemia, as well as liver cancer, squamous cell skin carcinomas, squamous cell cancers of the head and neck and other cancers. In their previous work, the scientists suspected that C/EBPα may act as a tumor suppressant in normal cells, but the mechanism by which its absence promoted lung cancer tumors remained unclear.

In a series of in vitro experiments, the researchers demonstrated that C/EBPα indeed works as a tumor suppressant by restraining the expression of another molecule known to play a role in triggering and maintaining tumor growth. This molecule, called BMI1, is an oncogenic protein that has been implicated in colon cancer, a form of leukemia and breast and gastric cancers.

To determine the relationship between the suspected tumor suppressor (C/EBPα) and the oncogenic protein (BMI1), the researchers first altered a line of human adenocarcinoma cells to overexpress C/EBPα. That led to a marked reduction in the expression of BMI1. When the team analyzed tissues from 261 patients with NSCLC, they found an inverse correlation between the two molecules; that is, more than 80 percent of patient tissues with low levels of the tumor suppressing C/EBPα were positive for BMI1 expression. Likewise, an analysis tissue samples from patients with lung adenocarcinoma with no or low C/EBPα expression revealed that those with lower levels of BMI1 were more likely to survive, a pattern that has prognostic value, the researchers wrote.

“Our findings suggest that the lung cancer subtype defined by the loss of C/EBPα expression might specifically benefit from therapies that inhibit BMI1,” the scientists wrote. “Thus, identifying factors that modulate its expression has generated major clinical interest.”

The research team was also able to validate its findings in mice. In one set of experiments with mice engineered to express no C/EBPα, the scientists found an inverse relationship between the transcription factor and BMI1 that was nearly identical to its data from human adenocarcinoma. By manipulating BMI1 expression in vivo, the researchers were also able to confirm that decreasing the expression of the oncogenic protein was enough to fully inhibit tumor formation and even significantly arrest tumor growth.

“BMI1 plays a substantial role in many solid tumors, including one of the most aggressive models of lung cancer, and its expression is linked with tumor growth, invasion, metastasis, prognosis and recurrence,” Levantini said. “Our findings could help us design better therapies for the subset of adenocarcinoma patients with low C/EBPα and high BMI1 expression pattern.”