Archive for the ‘Press Release’ Category

American Society for Biochemistry and Molecular Biology

Scientists at Harvard Medical School and the Dana-Farber Cancer Institute have developed a method that exploits the multitargeted nature of a chemical inhibitor to pinpoint vulnerabilities within cancer cells.

When signaling pathways within cells are triggered, proteins activate through a chain reaction, like a row of tumbling dominoes, until the final protein influences some cellular function. In some tumors, multiple signaling pathways drive cell growth and survival. This redundancy means that if one pathway ceases activity, another could continue driving cancerous behavior. Thus, drugs with the ability to shutdown multiple pathways at the same time could be advantageous.

Many cancer drugs, including some clinically approved kinase inhibitors, were originally designed to block the function of specific molecules but it is now known that their benefits might not always stem from the inhibition of single targets.

“Many of these covalent inhibitors are in fact some degree polypharmacological in their action and they can target multiple things,” said Nathanael Gray, a professor of biological chemistry and molecular pharmacology at Harvard Medical School and the Dana Farber Cancer Institute in Boston, Massachusetts. “They’re advertised as working through one target, but people in the field know that several other targets contribute.”

In a study published in the Journal of Biological Chemistry, a team researchers led by Gray identified key molecules that support the survival of a specific type of lung cancer cells. By analyzing the response of these cells to a cancer-killing kinase inhibitor with numerous targets, they were able to show that the anticancer effects were likely elicited by simultaneous inhibition of specific molecules in two signaling pathways. This approach to drug-target discovery could be useful for designing drugs that selectively attack multiple proteins, which is beneficial for managing certain tumors.

Although kinase inhibitors hit multiple targets, most were not designed to do so, which means they might bind to molecules unnecessarily and lead to adverse effects. And because it has been unclear which combinations of targets would have the most desirable effects, it has been challenging for researchers to purposefully design multitargeted drugs for cancer, Gray said.

To allow better drug design, Gray sought to discover which of the many buttons pushed by these inhibitors enables their anticancer effects. In a study to be published later this year, Gray and his lab investigated the kinase inhibitor SM1-71 and, using a suite of chemical proteomic and cellular techniques, showed that it actually binds to dozens of kinases, some of which are involved in critical signaling pathways that support cell survival and growth.

“It was sort of like a stick of dynamite and really could hit a lot of different targets,” Gray said.

In the study published in JBC, the researchers exposed different types of cancer cells to SM1-71 and found that the drug was highly toxic to a specific line of lung cancer cells with mutated KRAS protein, which is common in some tumors and leads to constant activation of signaling pathways that drive cell growth. The ability of the inhibitor to kill these cells in spite of this mutation suggested that targets in several pathways were being hit, Gray said.

To find which inhibitory interactions were curbing cancer activity, the researchers first identified which kinases in their previously generated list of SM1-71 targets were known to be key signaling proteins for cell growth and survival. They then narrowed down these candidates with Western blotting, which showed if any of these proteins from the cancer cells were actually being inhibited, and saw that proteins in two critical pathways were indeed being blocked.

The authors then applied various kinase inhibitors used in research and the clinic to see if specifically inhibiting any combination of these proteins would replicate the effects that SM1-71 had on the cancer cells. In the end, inhibiting MEK1/2 and IGF1R/INSR proteins at the same time demonstrated similar effects, suggesting these are crucial targets in this lung cancer line, Gray said.

SM1-71 itself would not likely be viable in humans because it binds to too many proteins and can lead to collateral damage, Gray said. But uncovering its most important targets within specific pathways could aid the design of future drugs that can shutdown multiple signaling pathways in tumors.

“The next step would be to try to preserve the efficacy driving targets while getting rid of targets that may be contributing to the toxicology,” Gray said.

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DOI: 10.1074/jbc.RA118.006805

This work was supported by National Institutes of Health Grants P50GM107618, U54-CA225088, and U54-HL127365; a Jonathan M. Goldstein and Kaia Miller Goldstein systems pharmacology fellowship; and a Linde Family gift.

Other authors on this study include Suman Rao, Guangyan Du, Marc Hafner, Kartik Subramanian and Peter K. Sorger.

American Society for Biochemistry and Molecular Biology Article: https://www.eurekalert.org/pub_releases/2019-04/asfb-uap040419.php

Journal of Biological Chemistry Paper: http://www.jbc.org/content/early/2019/03/11/jbc.RA118.006805

About the Journal of Biological Chemistry

JBC is a weekly peer-reviewed scientific journal that publishes research “motivated by biology, enabled by chemistry” across all areas of biochemistry and molecular biology. The read the latest research in JBC, visit http://www.jbc.org/.

About the American Society for Biochemistry and Molecular Biology

The ASBMB is a nonprofit scientific and educational organization with more than 11,000 members worldwide. Most members teach and conduct research at colleges and universities. Others conduct research in government laboratories, at nonprofit research institutions and in industry. The Society publishes three journals: the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics. For more information about ASBMB, visit http://www.asbmb.org.

Posted in News Article, Press Release | Comments Off on Using a Promiscuous Inhibitor to Uncover Cancer Drug Targets

Benefits of many cancer drug combinations not due to interactions between drugs, but to a form of bet hedging

At a glance:

  • Survival benefits of many cancer drug combinations are not due to drug synergy, but to a form of “bet hedging.”
  • Combination treatment gives each patient multiple chances of responding to at least one drug, increasing overall measures of survival within patient populations.
  • Computational models of combinations in which drugs act independently of each other accurately predict survival.
  • Findings suggest new ways to interpret clinical trial data, identify truly synergistic drug pairings and improve the design of combination therapies.

The efficacy of many FDA-approved cancer drug combinations is not due to synergistic interactions between drugs, but rather to a form of “bet hedging,” according to a new study published by Harvard Medical School researchers in Cell on Dec. 14.

Reanalyzing data from 15 clinical trials, the researchers show that independent action—in which drugs do not enhance each other’s effectiveness—can accurately explain gains in survival for most combination cancer therapies when compared to single-drug treatments.

Genetic variations in cancer from one person to another lead to differences in drug response, the researchers said, and treating populations of patients with multiple drugs boosts the likelihood that a patient will benefit from at least one of them.

The finding differs from current hypotheses about drug interaction, which have commonly attributed benefits to drug synergy. However, this should not be interpreted as diminishing the value of combination therapy for patients, the team cautions. Instead, they argue that exploiting drug independence represents a powerful approach for developing better combinations and treatment strategies in the absence of a complete understanding of disease.

A focus on maximizing the odds of a patient responding to at least one drug, for example, could support treating patients with drugs sequentially instead of simultaneously, thereby reducing compounding side effects, enabling higher dosages when effective and potentially lowering treatment costs.

“Our study provides a conceptual framework for rethinking how and why drugs should be given in combination,” said senior study author Peter Sorger, the Otto Krayer Professor of Systems Pharmacology at HMS and director of the Harvard Program in Therapeutic Science and the Laboratory of Systems Pharmacology.

“Independent action offers a simpler and more satisfactory explanation that can help physicians use existing drugs better, help patients have fewer adverse effects and help drug companies develop better combinations that fully realize the promise of precision medicine,” Sorger added.

These arguments underscore the importance of developing new methods to identify which patients respond best to which drug and to maximize the odds of treatment success.

“Positive results for combination cancer therapies have commonly been interpreted as patients needing two or more drugs to shrink their tumors and for them to get better, but our analysis suggests this is often not the case,” said study author Adam Palmer, research fellow in therapeutic science at the Laboratory of Systems Pharmacology. “Many patients are likely responding to only one of the drugs, and the other may be doing little to nothing but generating toxic side effects.”

Perspective Shift

Combination therapies are a mainstay of modern cancer treatment, supported by numerous clinical trials showing that patients who receive two or more drugs respond better than those who get single-drug therapy.

The design of most combinations is based on a sound biological rationale: Drugs targeting the same or complementary molecular pathways should be able to enhance each other’s efficacy. This additive or synergistic effect is thought to render tumors less resistant to treatment and allow the use of lower doses to lessen toxicity.

Due to the genetic and molecular variability of human cancers, it is difficult to predict whether a treatment will be effective for any individual patient. This unpredictability holds true even for cancer therapies tested on different tumor cell cultures in controlled laboratory experiments. Prompted by this observation, Palmer and Sorger investigated whether this variability contributes to the clinical efficacy of drug combinations.

To do so, they reanalyzed human clinical trial data where combination and single therapies were compared.

For example, a recent phase 3 trial of two FDA-approved immunotherapy drugs for melanoma—ipilimumab and nivolumab—found that combination therapy allowed half of the patients to survive longer than 13 months without their disease getting worse. In comparison, half of the patients treated with either agent alone survived longer than three and seven months, respectively, with their disease kept at bay.

Next, Palmer and Sorger used computational models to simulate how patients would fare if they had received treatment with only the drug that was better matched to their individual tumor. The team predicted that half of the patients in this scenario should survive longer than 14 months without worsening disease, a number that nearly mirrored the actual clinical trial outcomes.

The pattern held true for the majority of trials they analyzed—including ovarian cancer, breast cancer, pancreatic cancer and metastatic melanoma—suggesting that independent drug action can explain the efficacy of many combination therapies. Roughly a third of the trial data did not match their simulations, suggesting that these cases represented truly synergistic drug interactions.

The team also analyzed a database in which dozens of combination and single therapies were tested on hundreds of human-derived tumors implanted in animals. Drug independence explained the superiority of combination therapies across nearly all drugs and tumor types in these experiments, the team found. If drugs were working synergistically, then the best personalized drug combinations should be more effective than the best personalized single therapies. The team’s analysis, however, revealed that survival for the best single treatments was statistically indistinguishable from the best combination therapies.

Future Framework

Within a diverse patient population treated with a two-drug combination, one group of patients will respond to one drug, one group to the other, one group to both and one group to neither. If it exists, drug synergy can only be identified in the small subset that responds to both drugs, which means that the majority of patients are benefiting only from independent action, Palmer and Sorger argue.

“We simulated what effects bet hedging with drugs that act independently would have on patient populations, and our models precisely agreed with the observed data,” Palmer said. “This analysis shifts the perspective for thinking about drug combinations from a molecular rationale to a probabilistic one. They are useful even when we cannot predict which patients need which drugs, a finding that is a strong argument for advancing precision medicine.”

This framework also allows researchers to identify truly synergistic drug combinations and better design clinical trials by estimating the baseline benefit of combinations if they are not synergistic. Drugs that enhance each other’s efficacy should exceed the benefits predicted by independent action.

“The fact that so many drugs conformed to this expectation tells us how much better drug combinations really could be,” Sorger said. “Our findings only emphasize how important it is that we improve our understanding of the mechanisms of drug action at the level of a single patient.”

“What we want when we combine drugs is a greater chance of hitting a home run and a reduction in adverse effects,” he added. “We should be focusing on how to identify which of the drugs a patient is responding to and get them off the other ones.”

During the course of their investigation, Palmer and Sorger found that the idea of independent action was not new but had, in fact, been proposed decades ago. Researchers in the 1950s and 1960s made the case that combination therapies could be used to overcome tumor variation, but the concept was marginalized as scientists focused on genetic and molecular rationales of synergy. The data was not then available to test these ideas however.

“Modern data science helped us rediscover a way of thinking about drugs given in combination, which we believe will help us develop new drugs and treat today’s patients,” Sorger said. “We realized how much we didn’t know about drug combinations when we looked at it more deeply. Scientific progress requires us to continuously reevaluate and improve on our ideas. Basic, fundamental studies can help come up with better practical solutions.”

This study was supported by a National Health and Medical Research Council of Australia Early Career Fellowship and the National Institutes of Health (GM107618).

Release written by Kevin Jiang

HMS Article: https://hms.harvard.edu/news/combination-rethink

Cell Paper: http://www.sciencedirect.com/science/article/pii/S0092867417313181

About Harvard Medical School
Harvard Medical School (http://hms.harvard.edu) has more than 11,000 faculty working in 10 academic departments located at the School’s Boston campus or in hospital-based clinical departments at 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System.

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We are proud to announce that Mariana Cárdenas-González and the Vaidya Lab’s research on kidney toxins and early indications of kidney injury in children has been featured in ScienceDaily and EurekAlert as well as the websites of Harvard Medical School and Brigham and Women’s Hospital!

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The overall goal of the HMS LINCS Center is to delineate the fundamental principles of cellular response to drugs and toxins at the level of single-cells and cell populations and to make response data routinely available on the web. The Center will develop, test and apply diverse measurement and computational methods and use these to create response signatures for multiple human cell types exposed to perturbations individually and in combination.

Posted in Press Release | Comments Off on LINCS (Phase II) Center in HiTS is funded with a $12.8 Million grant from NIGMS

The grant will allow HiTS scientists to participate in a nationwide consortium that will build advanced algorithms to accumulate and make sense of the vast biomedical literature databases on the internet.  The new system will learn from the literature and become a self-updating resource for understanding and hypothesis creation across all domains, beginning with cancer biology.

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VSVaidya

 Dr. Vishal S. Vaidya

Harvard Professor Wins Society of Toxicology

Leading Edge in Basic Science Award

 Reston, Va.; March 17, 2014 — In honor of discoveries that illuminate the heart of toxicology, the Society of Toxicology (SOT) presents Harvard Medical School’s Vishal S. Vaidya, PhD, with the 2014 SOT Leading Edge in Basic Science Award. With this award, SOT, a professional association of more than 7,700 toxicologists,annually honors a scientist whose recent research has made seminal contributions to understanding the fundamental mechanisms of the science of toxicology. Dr. Vaidya will be formally presented with his peer-nominated award at SOT’s 53rd Annual Meeting and ToxExpo in Phoenix, Ariz., on March 23, 2014, and will deliver a lecture on March 25, 2014.

“Dr. Vaidya’s work over the past five years will change the way textbooks are written and science is conducted with respect to deploying biomarkers for monitoring kidney damage,” says nominator Frank D. Sistare, PhD. “His research has set a high standard for future safety biomarker qualification efforts, while demonstrating the tremendous value that such efforts can bring to drug development.”

The SOT Leading Edge in Basic Science Award recognizes Dr. Vaidya for his work with a protein known as kidney injury molecule-1 (Kim-1) as a biomarker for kidney injury, including developing new tools for biomarker detection. Due, in part, to the research of Dr. Vaidya and his colleagues, Kim-1 is now an accepted biomarker by the U.S. Food & Drug Administration (FDA), European Medical Agency, and Japanese Agency for ascertaining renal injury during drug discovery tests. His work also led to the development of a bedside test for monitoring Kim-1 levels in preclinical and clinical settings.

Dr. Vaidya leads the Systems Toxicology Program within the Harvard Program in Therapeutic Sciences and directs the Laboratory of Kidney Toxicology and Regeneration at Brigham and Women’s Hospital. His laboratory uses cellular systems, mouse models, as well as human biospecimens, and applies methodologies at the interface of bioinformatics, cell & molecular biology, systems toxicology, and translational science in understanding kidney disease. Dr. Vaidya has authored more than 55 peer-reviewed publications, including original research articles, reviews, and book chapters with more than 3,500 citations and an h-index of 32. Dr. Vaidya has served as a guest editor of a special issue of “Biomarkers of Toxicity” for the journal

Toxicology [2008; 245(3): 163-224], and he has also served as a primary editor for the book Biomarkers in Medicine, Drug Discovery and Environmental Health, published by John Wiley and Sons, N.Y., in 2010. He is the recipient of the NIH Outstanding New Environmental Scientist Award and Burroughs Wellcome Fund’s Innovation in Regulatory Science Award.

Dr. Vaidya received his BS in pharmacy from India’s Poona College of Pharmacy and his PhD in toxicology from the University of Louisiana at Monroe.

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About SOT

Founded in 1961, the Society of Toxicology (SOT) is a professional and scholarly organization of more than 7,700 scientists from academic institutions, government, and industry representing the great variety of individuals who practice toxicology in the US and abroad. SOT is committed to creating a safer and healthier world by advancing the science of toxicology. The Society promotes the acquisition and utilization of knowledge in toxicology, aids in the protection of public health, and has a strong commitment to education in toxicology and to the recruitment of students and new members into the profession. For more information about SOT and toxicology, visit the Society online at www.toxicology.org.

 

Media Contact: Michelle Werts Society of Toxicology

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