Sees Higher Guidance
Monday, October 8, 2018
Analysis reveals genomic effects of a new cancer treatment now in clinical trials
A twist on the molecular mechanism of how a new cancer drug works could aid in better identifying the best treatments for patients for an array of cancers. The finding is described in Molecular Cell in a study led by Eric J. Brown, PhD, an associate professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania.
Using mouse and human cells, Brown’s team, including co-first authors Nishita Shastri and Yu-Chen Tsai, identified over 500 sites in DNA that require an enzyme called ATR checkpoint kinase to not break when they are replicated. These sites are characterized by stretches of repeating DNA building blocks, which impede the normal replication of DNA. The harmful impact of these “genomic potholes” are lessened when the ATR kinase goes to work as a virtual “shock absorber” to smooth over the bumpy parts of replication. Importantly, inhibitors of ATR cause DNA to break, which is key to the anti-cancer effects of this drug.
ATR and PARP enzymes are part of the DNA Damage Response (DDR), which is used by cancer cells to survive high levels of replication stress and defects in DNA repair. Because cancers rely on the DDR for survival, stopping this process with ATR inhibitors is more toxic to cancer cells than normal cells. As such, DDR drugs such as ATR and PARP inhibitors may be more effective than standard therapies.
“Customized clinical use of DDR inhibitors is frequently based on changes in the level or function of specific proteins in cancer cells and this approach aims to improve treatment efficacy,” Brown said. “However, it is possible that the effects of ATR inhibitors may not be solely based on lethal interactions with defective gene expression in cancer cells, but also on the state of the repetitive DNA that relies on the ATR enzyme for stability.”
ATR inhibitors are in clinical trials for a variety of cancers, including lung, colon, pancreatic, lymphoma, leukemia and others. Penn recently opened a clinical trial, led by Fiona Simpkins, MD, an associate professor of Obstetrics and Gynecology, to investigate the benefit of combining ATR inhibitors with PARP inhibitors for the treatment of recurrent ovarian cancer. “ATR inhibitors may help PARP inhibitors work more effectively during different clinical situations, including overcoming PARP inhibitor resistance,” Simpkins said.
“While it is too early to tell exactly how detecting specific DNA sequences that break due to ATR inhibition will be applied in the clinic, the idea that the genome itself, not just the proteins expressed from it, might influence responses to treatment is a novel concept worthy of exploration,” Brown said.
The Penn team plans to monitor these sites of repetitive DNA as part of the ATR inhibitor combination clinical trial, which seeks to identify biomarkers that will maximize treatment efficacy.
This project was funded by the National Institute of Health (2R01AG027376, 1R01CA189743, 5R25CA101871, T32ES019851, 1R15CA208676), the Basser Center for BRCA Research, the Pennsylvania Department of Health, Center of Excellence in Environmental Toxicology, and the Abramson Family Cancer Research Institute.
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Materials provided by University of Pennsylvania School of Medicine. Note: Content may be edited for style and length.
Journal Reference:
- Nishita Shastri, Yu-Chen Tsai, Suzanne Hile, Deondre Jordan, Barrett Powell, Jessica Chen, Dillon Maloney, Marei Dose, Yancy Lo, Theonie Anastassiadis, Osvaldo Rivera, Taehyong Kim, Sharvin Shah, Piyush Borole, Kanika Asija, Xiang Wang, Kevin D. Smith, Darren Finn, Jonathan Schug, Rafael Casellas, Liliya A. Yatsunyk, Kristin A. Eckert, Eric J. Brown. Genome-wide Identification of Structure-Forming Repeats as Principal Sites of Fork Collapse upon ATR Inhibition. Molecular Cell, 2018; DOI: 10.1016/j.molcel.2018.08.047
Novel tech enables early lung cancer detection when surgical cure is possible
Non-small-cell lung carcinoma (NSCLC) is often fatal because most cases are not diagnosed until they are so advanced that surgical intervention is no longer possible. To improve outcomes researchers are developing a blood test to detect lung cancer earlier in the disease. A report in The Journal of Molecular Diagnostics describes a new technology, electric field-induced release and measurement (EFIRM) that is both highly sensitive and specific in detecting two epidermal growth factor receptor (EGFR) mutations associated with lung cancer in the blood of NSCLC patients with early-stage disease. This platform is relatively inexpensive and capable of high-throughput testing.
Despite advances in chemotherapy, five-year survival for patients diagnosed with unresectable NSCLC is less than 10 percent. The ability to diagnose NSCLC in stages 1 and 2, when surgical resection and potential cure are still possible, could significantly reduce the mortality from NSCLC worldwide. “The revolutionary EFIRM technology is the most exciting development in noninvasive liquid biopsy in recent years. The potential to detect early-stage lung cancer patients with an affordable blood or saliva test could save thousands to tens of thousands of lives annually worldwide,” stated Charles M. Strom, MD, PhD, co-director of the Center for Oral/Head and Neck Oncology Research at the UCLA School of Dentistry, Los Angeles, CA, USA, and Senior Vice President and Chief Medical Officer of EZLife Bio, USA, Woodland Hills, CA, USA. The EFIRM technology can also be used to monitor treatment and detect recurrence in patients already diagnosed with NSCLC.
Previously, the investigators had successfully measured two actionable EGFR mutations (p.L858R and Exon 19del) in blood samples from patients with late-stage NSCLC using EFIRM technology. In the current study, they investigated whether the mutations could be found in samples from patients with early-stage disease.
The researchers collected plasma samples from 248 patients with radiographically-determined pulmonary nodules. Of those, 44 were diagnosed with Stage I or Stage II NSCLC (23 with biopsy-proven benign pulmonary nodules and 21 with Stage I or Stage II adenocarcinoma). EFIRM was able to detect the p.L858R mutation in 11 of 12 samples and the Exon 19del mutation in seven of nine samples, resulting in greater than 90 percent sensitivity and 80 percent specificity.
“Currently, the clinical sensitivity of EFIRM to detect patients with NSCLC is limited by the percentage of tumors containing either or both of the two variants, which is estimated at 27 percent of NSCLC tumors,” explained co-investigator Wu-Chou Su, MD, of the Department of Internal Medicine, National Cheng Kung University Hospital and College of Medicine of the National Cheng Kung University, Tainan, Taiwan. “We are presently developing a 10-variant panel that contains detecting mutations expressed in 50 percent of all lung malignancies.”
Investigators emphasize that this study does not present direct evidence that detecting EGFR mutations in the plasma of an individual is predictive that the patient has cancer. Future work will explore whether finding an EGFR mutation in the circulation has any predictive value. Currently, the EFIRM liquid biopsy may be helpful for guiding treatment selection in patients for whom biopsy material is not available.
“We are gratified by the performance of the EFIRM platform in patients whose tumors were still small enough to qualify for surgical care. Work is underway to increase the number of mutations analyzed and to automate the process to increase sensitivity and facilitate mass screening,” commented Dr. Strom.
Story Source:
Materials provided by Elsevier. Note: Content may be edited for style and length.
Journal Reference:
- Fang Wei, Charles M. Strom, Jordan Cheng, Chien-Chung Lin, Ching-Yun Hsu, Guy W. Soo Hoo, David Chia, Yong Kim, Feng Li, David Elashoff, Tristan Grognan, Michael Tu, Wei Liao, Rena Xian, Wayne W. Grody, Wu-Chou Su, David T.W. Wong. Electric Field–Induced Release and Measurement Liquid Biopsy for Noninvasive Early Lung Cancer Assessment. The Journal of Molecular Diagnostics, 2018; DOI: 10.1016/j.jmoldx.2018.06.008
Arcus Biosciences to present Phase 1 AB928 study at ESMO
Arcus Biosciences announced that it will present final results from the Phase 1 study of AB928, its dual adenosine receptor antagonist, in healthy volunteers during a poster display session at the European Society of Medical Oncology 2018 Congress, being held October 19-23, 2018, in Munich, Germany. The safety data to be presented will demonstrate that in this study, there was no evidence of the physiological effects of blocking adenosine that have been observed clinically with earlier adenosine receptor antagonists. Physiological effects associated with the earlier adenosine receptor antagonists that were initially designed for CNS indications may potentially limit their optimal dosing in the oncology setting. The pharmacokinetic and pharmacodynamic correlations generated from this study, which will be described in the poster presentation, were used to guide dose selection in the Company’s four Phase 1/1b trials in patients.
https://thefly.com/landingPageNews.php?id=2801253
Study suggests novel approach to treating adults with autism spectrum disorder
A team of scientists at Florida Atlantic University has uncovered a brain-signaling pathway that can be pharmacologically manipulated in genetically engineered mice to reverse an autism-related pathway. Using an investigational drug targeting this pathway, the researchers normalized the disrupted physiology and behavior of these mice. Moreover, effects were seen in adult mice, suggesting a possible route to medication development for adults with autism spectrum disorder (ASD).
Currently, there are no FDA-approved medications that improve the core symptoms of ASD. Findings from this study, published in the Proceedings of the National Academy of Sciences (PNAS), suggest a novel approach to treating this disorder in some people by targeting an enzyme normally associated with stress and inflammation.
The study was based on decades of research by the team on serotonin, a mood-regulating molecule in the brain that regulates many brain synapses – the gaps between nerve cells where signals are sent and received. The supply of serotonin is tightly regulated by a protein called the serotonin transporter (SERT), which sweeps away serotonin from synapses to limit its action. Shifts in the transporter’s activity can have significant consequences on the ability of serotonin to act in the brain.
While evidence shows that changes in SERT expression and function may underlie risk for neuropsychiatric disorders, exactly how SERTs are normally regulated in the brain and whether this regulation can be a target for improved medications, and for what disorders, has been unclear.
Randy Blakely, Ph.D., senior author, executive director of FAU’s Brain Institute, and a professor of biomedical science in FAU’s Schmidt College of Medicine, first identified and cloned the human SERT gene about 25 years ago and established the ability of SERT to be blocked by the major antidepressant medications such as Prozac®, Zoloft® and Lexapro®. Recognizing the limits of these medications, Blakely hypothesized that resetting the normal regulation of SERT, rather than eliminating its function altogether, might be a more subtle and effective way to modify brain serotonin signaling.
“We suspected that normally as serotonin signaling changes, neurons turn up or down the activity of this transporter keeping serotonin levels finely balanced,” said Blakely. “We generated evidence for this idea using cultured cells that expressed SERT, but what these observations meant for the brain or brain disorders was unclear.”
In 2005, Blakely and collaborators at Vanderbilt University reported multiple mutations in SERT in children with ASD. Remarkably, all of these mutations made the transporter hyperactive all of the time, like an out-of-control vacuum cleaner sucking the air out of a room.
“Our years of studying SERT gave us a clue as to how to tone down SERT hyperactivity without eliminating the protein’s normal function,” said Blakely.
A few years before their mutation discovery, Blakely’s team identified an enzyme, p38α MAPK, as a key SERT regulator. This enzyme is well known to be a contributor to inflammatory responses, but work from multiple laboratories suggests that the enzyme plays a role in the normal control of serotonin signaling. Importantly, changes in molecules linked to p38α MAPK signaling have been reported in brain samples from ASD subjects. Focusing on the most common of the SERT mutations, Ala56, the group set out to test their theory that SERT was being shoved into “high gear” by the enzyme.
With genetic engineering approaches, the team introduced the Ala56 mutation into the genome of a mouse, where brain biochemistry, physiology and behavior could carefully be examined. As predicted, SERT was found to be modified excessively by p38α MAPK.
Moreover, they found changes in the behavior of the mice that were reminiscent of some features of ASD. These changes included excessive repetitive behaviors, deficits in communication, and diminished social interactions. In addition, they found elevated serotonin levels in the blood of the mice, a change seen in 25-30 percent of subjects with ASD – the first time the trait had been reproduced in animals generated to mimic ASD.
“The studies primarily told us that Ala56 wasn’t a benign mutation and possibly that the mice might provide a testbed for developing novel serotoninergic medications,” said Blakely.
To test this idea, Blakely needed a drug that could attack brain p38α MAPK potently and specifically. Biochemist D. Martin Watterson, Ph.D., at the Department of Pharmacology at Northwestern University Feinberg School of Medicine and a co-author, came up with the needed tool known as MW150.
“Marty’s drug was really key to our efforts, as it gets into the brain very well, has good selectivity for p38α MAPK, and previously had been demonstrated to be safe to use in animals,” said Matthew J. Robson, Ph.D., first author and an assistant professor in the James L. Winkle College of Pharmacy at the University of Cincinnati. “Remarkably, giving the drug once a day for a week reversed many of the changes induced by the SERT Ala56 mutation.”
Encouraged by these findings, yet knowing that drugs can sometimes act on other targets, Blakely’s team sought another approach to confirm that the drug’s effects were due to blockade of brain p38α MAPK. They decided to eliminate the enzyme only from brain serotonin neurons using a genetic approach called “conditional gene deletion.” The effects with animals lacking a functional p38α MAPK gene mirrored their findings with MW150.
“Although serotonin and SERT are active in the brain throughout development, one key finding of our study is that the effects we saw with MW150 were found in adult mice,” said Robson. “When people think about treating ASD, they generally think about medications for children. While we do not know if our strategy will lead to new medications, treatments that can help adults with ASD is clearly a huge unmet need.”
The diagnostic features of ASD are behavioral in nature, yet medical comorbidities are common, including bowel problems such as constipation. In 2016, Blakely and a team of researchers at Columbia University led by Kara Margolis, M.D. and Michael Gershon, M.D., co-authors, demonstrated that in addition to behavioral problems, the SERT Ala56 mice showed poor development of the nerve cells that line the colon and support gut contractions. Astonishingly, Blakely’s study demonstrated that MW150 also could treat physiological changes linked to gut function in the mice.
“Even though the first connections between serotonin and ASD were made more than 50 years ago, how we might tap into these observations for potential treatments hasn’t been clear,” said Blakely. “We think our study suggests a new direction for medication development, particularly if we can identify those patients where changes in brain serotonin make a difference.”
The SERT Ala56 mutation is relatively rare and found in only about 1 percent of the U.S. population. Even though Blakely’s human studies found the DNA change to be associated with traits of ASD, other individuals in the study who carried the variant did not have ASD.
“We don’t think the variant is a cause for ASD in many people; only in those where other genetic or environmental changes have occurred. The bigger message is that serotonin’s role in brain disorders likely goes far beyond depression,” said Blakely.
Blakely suggests the use of brain-imaging techniques that can scan for changes in SERT levels, or changes in serotonin signaling, could be a possible aid in identifying the right patients for treatment.
Recent estimates indicate a prevalence of ASD in the U.S. of 1 in 59 children with a well-established 4:1 male predominance. Individual costs for care are estimated at about $2.4 million, yielding a societal burden that is expected to exceed $400 billion by 2025.
“It’s been a long road with our research efforts,” said Blakely. “Although our studies so far have used mice, and there is still much to do to understand the full significance of the work, I am glad we haven’t veered from the path. I’m hopeful that our work will prove meaningful beyond the laboratory.”
ImmunoGen Has Initial Data from Antibody-Keytruda Combo at ESMO
ImmunoGen, Inc., (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, today announced that initial findings from the FORWARD II expansion cohort of mirvetuximab soravtansine in combination with Merck’s anti-PD-1 therapy, KEYTRUDA® (pembrolizumab), will be presented at the European Society for Medical Oncology (ESMO) Congress from October 19-23, 2018 in Munich, Germany. The poster will include initial safety and preliminary anti-tumor activity for 46 patients with platinum-resistant ovarian cancer (PROC), of whom 35 have medium or high folate receptor alpha (FRα) expression.
Encouraging activity and favorable tolerability data from the FORWARD II dose-escalation cohort assessing mirvetuximab soravtansine in combination with KEYTRUDA in 14 heavily pre-treated patients with platinum-resistant epithelial ovarian cancer (EOC) were presented in March at the Society of Gynecologic Oncology (SGO) Annual Meeting. These findings supported enrollment of additional patients in an expansion cohort with full doses of both agents to further evaluate this combination in PROC.
“Based on the data presented at SGO, we advanced mirvetuximab soravtansine plus pembrolizumab into an expansion cohort focusing on PROC patients with medium and high FRα expression,” said Anna Berkenblit, M.D., Vice President and Chief Medical Officer of ImmunoGen. “We look forward to presenting initial findings at ESMO, as we evaluate several combinations that may ultimately enable us to treat more women with ovarian cancer.”
Lilly to Present New Data From Oncology Portfolio at ESMO 2018 Congress
Eli Lilly and Company (NYSE: LLY) will present new data from its clinical development program at the European Society for Medical Oncology (ESMO) 2018 Congress in Munich, Germany, October 19-23. Data presented showcase how Lilly is taking a global, patient-centric research approach to drive advances in cancer care. Data include presentations on abemaciclib, pemetrexed and ramucirumab, as well as investigational compound pegilodecakin – used as a single agent and in combination with chemotherapy and with checkpoint inhibitor therapy – across multiple tumor types. Pegilodecakin joined the Lilly Oncology pipeline with the company’s acquisition of ARMO BioSciences earlier this year.
Key abemaciclib data include findings from the Phase 3 MONARCH 2 trial evaluating abemaciclib plus fulvestrant in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Additionally, results will be presented from Lilly’s ongoing immuno-oncology clinical collaboration with Merck (known as MSD outside the U.S. and Canada) on the KEYNOTE-189 trial evaluating pemetrexed plus platinum chemotherapy in combination with pembrolizumab in the first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC). Ramucirumab data include Phase 3 findings from several patient populations with aggressive disease such as the REACH-2 study of ramucirumab as a single agent in the second-line treatment of people with hepatocellular carcinoma (HCC), also known as liver cancer, and the RANGE study evaluating ramucirumab in combination with docetaxel in patients with locally advanced or unresectable or metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy. Pegilodecakin data include new results from an early-phase study in patients with renal cell, non-small cell lung, pancreatic, ovarian and breast cancers.
“The breadth and depth of our data being presented at ESMO underscores this year’s congress theme of ‘securing access to optimal cancer care’ by demonstrating how we are working to develop innovative new medicines that will make a difference to patients and doctors,” said Maura Dickler, M.D., vice president, late phase development, Lilly Oncology. “We’re also excited to share data for the first time from our promising next generation clinical immunotherapy asset pegilodecakin, which examines its potential in several tumor types in combination with existing treatments and as a monotherapy. We are encouraged by the results and look forward to further investigating pegilodecakin in a wide range of settings.”
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