Breaking News
March 19, 2019 - Heart attack patients who are taken to heart care centres directly survive longer
March 19, 2019 - IVF babies have increased in birthweight over the past 25 years, study reveals
March 19, 2019 - Study highlights the need for psychiatric care to be integrated into cancer treatment
March 19, 2019 - Testosterone treatment lowers recurrence rates in low-risk prostate cancer patients
March 19, 2019 - Caterpillars could hold the secret to new treatment for Osteoarthritis
March 19, 2019 - Parkinson’s treatment delivers a power-up to brain cell ‘batteries’
March 19, 2019 - Stanford launches new Institute for Human-Centered Artificial Intelligence
March 19, 2019 - Wireless earphones may cause cancer
March 18, 2019 - ACC/AHA guideline for prevention of cardiovascular disease released
March 18, 2019 - UTA nursing professor receives $6.575 million to attack musculoskeletal diseases
March 18, 2019 - Gene medication shows promise to treat spinal cord injuries
March 18, 2019 - First Human Study of “Robotic” RaniPill™ Capsule to Replace Injections Announced by Rani Therapeutics
March 18, 2019 - Food Allergy Testing: MedlinePlus Lab Test Information
March 18, 2019 - Altered brain activity patterns of Parkinson’s captured in mice
March 18, 2019 - Apple Heart Study demonstrates ability of wearable technology to detect atrial fibrillation | News Center
March 18, 2019 - Cardiovascular benefits of diabetes drug extend across a wide spectrum of patients, shows study
March 18, 2019 - Novel cardiac pump shows superior outcomes in patients with advanced heart failure
March 18, 2019 - U.S. FDA Grants Priority Review for Fedratinib New Drug Application in Myelofibrosis
March 18, 2019 - Living like a caveman won’t make you thin—but it might make you healthy
March 18, 2019 - Modified immune cells issue alert when detecting cancer in mice | News Center
March 18, 2019 - Dementia caregivers design robots for alleviating stress and increasing joyful moments
March 18, 2019 - VR technology could help improve balance in humans
March 18, 2019 - Study demonstrates effective way to slow progression of cerebrovascular disease in older adults
March 18, 2019 - Premature babies also have protective anti-viral antibodies
March 18, 2019 - Painkillers taken by pregnant mothers unlikely to cause asthma in the child
March 18, 2019 - Fibromyalgia can be reliably detected in blood samples
March 18, 2019 - Marijuana use has dropped among most teens after legalization
March 18, 2019 - Legacy Pharmaceutical Packaging, LLC Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP, 25mg, 50mg, And 100mg Due to The Detection of Trace Amounts Of N-Nitroso N-Methyl 4-Amino Butyric Acid (NMBA) Impurity Found in The Active Pharmaceutical Ingredient (API)
March 18, 2019 - Researchers identify early home and family factors that contribute to obesity
March 18, 2019 - Fate and festivity: Match Day 2019
March 18, 2019 - Study finds TAVR to be as good as open-heart surgery for patients at low surgical risk
March 18, 2019 - EU-funded project is developing new tools for diagnosing cancer
March 18, 2019 - Gluten, lactose, food dyes in pills could be causing side effects finds study
March 18, 2019 - Taking painkillers during pregnancy is not responsible for asthma risk in children, study shows
March 18, 2019 - Prediagnosis Psychiatric Care Linked to Worse Cancer Mortality
March 18, 2019 - Paris hospital halts stool study after donor deluge
March 18, 2019 - Partial oral antibiotic therapy shows efficacy and safety in patients with infectious endocarditis
March 18, 2019 - Olympus improves access to science education through BioBus collaboration
March 18, 2019 - Depression screening does not improve quality of life in heart attack patients
March 18, 2019 - Echocardiography may aid in patient selection for TMVR
March 18, 2019 - Are ‘Inactive’ Ingredients in Your Drugs Really So Harmless?
March 18, 2019 - Wearable technology can safely identify atrial fibrillation
March 18, 2019 - Scientists tackle rare retinal disease in unique research project
March 18, 2019 - Death By A Thousand Clicks
March 18, 2019 - Absorbable, antibiotic-eluting envelope can reduce rate of cardiac device infections
March 18, 2019 - Hormonal treatment associated with depression in men with prostate cancer
March 18, 2019 - Porvair Sciences launches reinforced 96-well deep round microplate
March 18, 2019 - Simplified catheter ablation could slash waiting lists for atrial fibrillation patients
March 18, 2019 - BFR therapy as part of rehabilitation following ACL surgery may slow bone loss
March 18, 2019 - A human model to test implants for cataract surgery
March 18, 2019 - New risk adjustment model could reduce financial penalty for safety net hospitals
March 18, 2019 - NHS cancer patients’ wait to start treatment worrying
March 18, 2019 - Inventiva Announces Results from Phase IIb Clinical Trial with Lanifibranor in Systemic Sclerosis
March 18, 2019 - Cologuard
March 18, 2019 - Researchers find evidence of prenatal environment tuning genomic imprinting
March 18, 2019 - Dolomite Bio launches novel Nadia product family for single-cell research
March 18, 2019 - Intellipharmaceutics Announces Resubmission of New Drug Application to the U.S. FDA for its Oxycodone ER
March 18, 2019 - Excessive gestational weight gain tied to maternal morbidity
March 18, 2019 - RCEM issues position statement on metrics to supplement four-hour standard target
March 17, 2019 - Noncontrast Brain MRI Effective for Monitoring Multiple Sclerosis
March 17, 2019 - Brain region plays key role in regulation of parenting behavior, study finds
March 17, 2019 - Natural speed limit on DNA replication sets pace for life’s first steps
March 17, 2019 - New research reveals overlooked impact of herbicide glyphosate on the environment
March 17, 2019 - Molecular patterns could help predict relapse risk in breast cancer patients
March 17, 2019 - Study confirms sensitivity of microbiological cultures for detecting cholera
March 17, 2019 - Scientists Spot Clues to Predicting Breast Cancer’s Return
March 17, 2019 - Scientists identify gene that keeps PTSD-like behavior at bay in female mice
March 17, 2019 - New method would allow doctors to detect earliest stages of cancers in the lymph nodes
March 17, 2019 - Cholesterol protein discovery raises hope for smarter drugs
March 17, 2019 - New insect medium delivers high viable cell density growth and protein yield
March 17, 2019 - Opioid crisis brings concerns about heart dangers
March 17, 2019 - Resistance Training May Prevent Type 2 Diabetes Progression
March 17, 2019 - Bioluminescence sensors make new approaches to drug discovery possible
March 17, 2019 - New FDA Rules Aim to Keep Kids From Flavored E-Cigarettes
March 17, 2019 - Vitamin B3 analogue boosts production of blood cells
March 17, 2019 - Government cuts to stop smoking services have detrimental impact on public health
March 17, 2019 - Common tool to assess potential adoptive parents lags behind societal changes
March 17, 2019 - Patients’ own cells could be the key to treating Crohn’s disease
March 17, 2019 - Diagnostic delays common in inflammatory bowel disease
March 17, 2019 - Study uncovers dramatic differences in the brains of Hispanics with dementia
Scientists develop novel computational framework to support personalized cancer treatment

Scientists develop novel computational framework to support personalized cancer treatment

image_pdfDownload PDFimage_print

Researchers at Columbia University Irving Medical Center (CUIMC) have developed a highly innovative computational framework that can support personalized cancer treatment by matching individual tumors with the drugs or drug combinations that are most likely to kill them.

The study, published today on Nature Genetics, by Dr. Andrea Califano of Columbia University Irving Medical Center and Dr. Irvin Modlin of Yale University and Wren Laboratories LLC, co-senior author on the study, with collaborators from 17 research centers worldwide, details a proof of concept for a novel analytical platform applicable to any cancer type and validates its predictions on gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The latter represent a rare class of tumors of the digestive system that, when metastatic, are associated with poor survival.

In a comprehensive analysis of samples from 212 patients, the team first identified a new class of drug-targets, called master regulators, which are rarely if ever mutated in cancer patients, and then predicted the drugs that can specifically invert their activity. Surprisingly, even though tumors were analyzed on an individual patient basis, the algorithm predicted the same top drug – Entinostat – for almost half of the metastatic patients. More importantly, when tested in a xenograft transplant of the tumor in a mouse, this drug induced dramatic shrinking of the tumor, while drugs predicted to have partial or no effect were also validated to produce results in line with predictions. These data led to rapid IND (Investigational New Drug) approval by the FDA for a metastatic GEP-NET clinical trial that is open and recruiting patients at Columbia University.

The innovative approach proposed in this manuscript, OncoTreat, is now available as a New York State Department of Health approved test through the Department of Pathology and Cell Biology at CUIMC. The test was co-developed with DarwinHealth, a precision oncology company born out of the Califano Lab work. It is the only such test designed to predict drugs that are optimally matched to individual patient tumors for 10 different aggressive tumor subtypes of ovarian, breast, pancreas, prostate, bladder, and lung cancer, as well as meningioma, sarcoma, glioblastoma, and GEP-NETs.

“This manuscript represents a first proof of concept of what may become a valuable new tool to deliver an effective and systematic precision medicine approach to cancer patients that may complement what we are currently doing with genetic mutations,” says Dr. Califano, the Clyde and Helen Wu Professor of Chemical and Systems Biology and chair of the Department of Systems Biology at CUIMC.

“Using novel systems biology methodologies, which combine the use of supercomputers with large-scale pharmacological assays, we can computationally predict and prioritize drugs and drug combinations that will most effectively kill cancer cells,” explains Dr. Califano. “Such an approach is especially promising for patients with aggressive tumors, who lack actionable mutations, fail to respond to targeted inhibitors or immune-checkpoint inhibitors, or relapse following initial response to a standard of care drug or drug combination. These patients, who unfortunately represent the majority of the aggressive tumor cases, present few, if any, effective therapeutic options. We hope that OncoTreat may offer the oncologist new alternatives when they run out of approved therapies, alternatives that are predicated on an increasingly mechanistic understanding of cancer cell regulation and response to drugs rather than on educated guesswork.”

Dr. Modlin, who had initially proposed the concept of addressing Neuroendocrine tumors using the innovative strategy developed by Dr. Califano, commented that the successful demonstration of the efficacy of a pre-treatment molecular identification strategy was a significant advance on previous practice where treatment agents were used based upon serendipitous selection rather than objective molecular evidence. This work combined with the use of molecular signature tools in blood to monitor real-time efficacy of therapy on disease are likely to change the face of therapeutic management in many diseases.

OncoTreat’s precision medicine approach

The OncoTreat framework centers on identifying and analyzing actionable proteins in cancer patients, independent of their genetic mutations. Called master regulators (MR), these proteins are organized into small regulatory modules – so-called tumor checkpoints – which are responsible for regulating and ensuring the stability of tumor cells. Master regulators and tumor checkpoints can be efficiently and systematically elucidated using the VIPER algorithm developed by the Califano Lab and published in an earlier Nature Genetics manuscript; critically, these analyses allow tracking their activity through metastatic progression, relapse, and development of drug resistance. These computational models were built based on mathematical concepts from information theory and Bayesian statistics and have been extensively validated over the past decade.

MR proteins represent a novel class of tumor vulnerabilities and potential therapeutic targets that are being increasingly adopted by pharmaceutical companies. Extensive research has demonstrated that shutting down the activity of these proteins is catastrophic for tumor cells, making it virtually impossible for them to survive and grow in their environment. In this study, drug compounds are prioritized based on their ability to revert the coordinated activity of 50 such master regulator proteins, as identified by the analysis of tumor samples. Predicted activity reversal was surveyed from an analysis of drug assays both in cell lines and in vivo, in PDX (Patient-Derived Xenografts) mice models.

“Master regulators–a new Achilles’ heel of cancer–represent the engine room of the cancer cell, where the effects of all tumorigenic mutations come together. What OncoTreat is able to do is attack this convergence point with a therapeutic intervention,” says collaborator Gary Schwartz, MD, division chief of hematology and oncology at CUIMC and associate director of the Herbert Irving Comprehensive Cancer Center. “By collapsing this tumor bottleneck, blocking this Achilles’ heel, the cancer can no longer survive. This method is so innovative, requiring a lot of mathematical modeling and understanding. It’s a whole new approach to cancer therapeutics, taking us in an entirely new direction.”

Califano and team validated the OncoTreat approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors, a deliberate choice since GEP-NETs are rare and poorly characterized, making them one of the more challenging tumors to research. Their analysis identified several MR proteins, including key immune function modulators, whose role as critical tumor dependencies was experimentally confirmed. The GEP-NET cells were screened against a library of 107 compounds, and found that the drug, Entinostat, proved to successfully invert the activity of the top 50 MR proteins in 42 percent of GEP-NET patients, providing the rationale for the follow up clinical trial.

“It is certainly our hope that this may provide a short cut to identify viable candidates for phase 2 trials in this and other malignancies,” says coauthor Edward Gelmann, MD, professor of medicine and of pathology and cell biology at CUIMC.

In addition to its potential therapeutic value, OncoTreat provides novel insight into the mechanisms and maintenance of GEP-NETs. In future work, Califano and collaborators intend to expand this approach to cover more than 80% of human malignancies and to develop clinical trials that will test the predictions in patients.

Source:

http://www.cumc.columbia.edu/

Tagged with:

About author

Related Articles