Stories about: drug discovery

Cancer researchers hit a bullseye with a new drug target for Ewing sarcoma

Cell staining shows the lethal efficacy of CDK+PARP inhibitors against Ewing sarcoma
Fluorescent staining shows how PARP and CDK12 inhibitors combine to deal a lethal blow to Ewing sarcoma. In the top row, green represents locations of DNA damage incurred by Ewing sarcoma cells. In the bottom row, red represents DNA repair activity. Together, PARP and CDK12 inhibitors lead to Ewing sarcoma cell death.

Screening a class of recently-developed drug compounds — so-called “CDK inhibitors” capable of blocking CDK7/12/13 proteins — against hundreds of different human cancer cell lines, researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center have found that CDK12 inhibitors pack a particularly lethal punch to Ewing sarcoma, a rare cancer typically affecting children and young adults.

“No one has previously considered CDK12 inhibition as a way to combat Ewing sarcoma,” says Kimberly Stegmaier, MD, senior author of the new Cancer Cell paper that describes the findings.

In 2014, Nathaneal Gray, PhD, co-author on the new paper, and his team were the first to develop CDK inhibitors.

Some individuals were entirely cured of the disease

“Now, in mice, we’ve shown that Ewing sarcoma cells die if CDK12 is knocked out genetically or chemically inhibited,” Stegmaier says. What’s more, her team has discovered that CDK12 inhibition can be combined with another drug, called a PARP inhibitor, to double down on Ewing sarcoma cells.

The revelation that CDK12 inhibition can kill Ewing sarcoma cells brings a surge of hope to the field of pediatric oncology, which has long been challenged to find new drugs against childhood cancers.

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Can rare pain syndromes point the way to new analgesics?

analgesic drug discovery could reduce prescription opioid use
Boston Children’s Hospital and Amgen will collaborate to discover and accelerate non-addicting pain drugs.

As the opioid epidemic deepens and drug overdoses increase, effective non-addicting painkillers are desperately needed. Efforts to discover new pain pathways to target with new drugs have thus far had little success. Other promising research is investigating triggerable local delivery systems for non-opioid nerve blockers, but it’s still in the early stages.

A new collaboration between Boston Children’s Hospital and the biopharmaceutical company Amgen is aimed at accelerating new pain treatments. Announced yesterday, it will revolve around patients with rare, perplexing pain syndromes. The scientists hope that the genetic variants they find in these patients will shed new light on pain biology and lead to new ways of controlling pain. 

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CRISPR enables cancer immunotherapy drug discovery

Artwork depicting cancer cells with different genes deleted by CRISPR-Cas9, performed to identify novel cancer immunotherapy targets
These cancer cells (colored shapes) each have a different gene deleted through CRISPR-Cas9 technology. In a novel genetic screening approach, the T cells (red) destroy those cancer cells that have lost genes essential for evading immune attack, revealing potential drug targets for enhancing PD-1-checkpoint-based cancer immunotherapy. Credit: Haining Lab 

A novel screening method using CRISPR-Cas9 genome editing technology has revealed new drug targets that could potentially enhance the effectiveness of PD-1 checkpoint inhibitors, a promising new class of cancer immunotherapy.

The method, developed by a team at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, uses CRISPR-Cas9 to systematically delete thousands of tumor genes to test their function in a mouse model. In findings published today by Nature, researchers led by pediatric oncologist W. Nick Haining, BM, BCh report that deletion of one gene, Ptpn2, made tumor cells more susceptible to PD-1 checkpoint inhibitors. Other novel drug targets are likely around the corner.

PD-1 inhibition “releases the brakes” on immune cells, enabling them to locate and destroy cancer cells. But for many patients, it’s not effective enough on its own.

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Souped-up fish facility boosts drug discovery and testing

closeup of zebrafish-20150526_ZebraFishCeremony-60The care and feeding of more than 250,000 zebrafish just got better, thanks to a $4 million grant from the Massachusetts Life Sciences Center to upgrade Boston Children’s Hospital’s Karp Aquatics Facility. Aside from the fish, patients with cancer, blood diseases and more stand to benefit.

From a new crop of Boston-Children’s-patented spawning tanks to a robotic feeding system, the upgrade will help raise the large numbers of the striped tropical fish needed to rapidly identify and screen potential new therapeutics. It’s all part of the Children’s Center for Cell Therapy, established in 2013. We put on shoe covers and took a look behind the scenes. (Photos: Katherine Cohen)

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Seeding medical innovation: The Technology Development Fund

Monique Yoakim Turk Technology Development FundMonique Yoakim-Turk, PhD, is a partner of the Technology Development Fund and associate director of the Technology and Innovation Development Office at Boston Children’s Hospital

Since 2009, Boston Children’s Hospital has committed $6.2 million to support 58 hospital innovations ranging from therapeutics, diagnostics, medical devices and vaccines to regenerative medicine and healthcare IT projects. What a difference six years makes.

The Technology Development Fund (TDF) was proposed to Boston Children’s senior leadership in 2008 after months of research. As a catalyst fund, the TDF is designed to transform seed-stage academic technologies at the hospital into independently validated, later-stage, high-impact opportunities sought by licensees and investors. In addition to funds, investigators get access to mentors, product development experts and technical support through a network of contract research organizations and development partners. TDF also provides assistance with strategic planning, intellectual property protection, regulatory requirements and business models.

Seeking some “metrics of success” beyond licensing numbers and royalties (which can come a decade or so after a license), I asked recipients of past TDF awards to report back any successes that owed at least in part to data generated with TDF funds. While we expected some of the results, we would have never anticipated such a large impact.

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Curbing metastasis in lung cancer by taking a cue from the nervous system

What's drawing lung cancer cells to migrate? (Juan Gaertner/Shutterstock)
What’s drawing lung cancer cells to migrate? (Juan Gaertner/Shutterstock)

Ninety percent of lung cancer deaths are caused by the tumor’s spread—or metastasis—to other organs. Researchers have now discovered an approach to blocking metastasis in the most common type of lung cancer, adenocarcinoma, that potentially could be added to chemotherapy treatments aimed at shrinking the primary tumor.

Kerstin Sinkevicius, PhD, a research fellow at Boston Children’s Hospital, started with this question: Is there anything in a lung tumor’s environment that makes it metastasize? She sampled tissue from human lymph nodes—the first place cancers typically spread to—to see if the cells there were secreting anything that might lure cancer cells to migrate.

One chemical stood out: a growth factor called brain-derived neurotrophic factor, or BDNF. Secreted near maturing neurons, BDNF is best known for its role in stimulating the developing nervous system.

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The Accelerating Medicines Partnership: Transforming biomedical consortia and R&D

Group handshake representing a consortiumDavid Altman is manager of marketing and communications in Boston Children’s Hospital’s Technology and Innovation Development Office.

Successful therapeutic development requires multiple stakeholders along the path from discovery to translation to clinical trials to FDA approval to market availability. At various points along this path, academia, industry, government, hospitals, nonprofits and philanthropists may work together. Would bringing these stakeholders together from start to finish lead to greater success?

A growing number of private-public consortia are launching in defined “pre-competitive” spaces where potential rivals collaborate to generate tools and data to accelerate biomedical research. In 1995, consortia were rare in health care: Only one was created. In 2012, 51 new consortia were launched, according to the organization Faster Cures.

Why? you may ask. Banding together in consortia can reduce costs, minimize failures and shorten the timeline to approval for new drugs.

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The obesity-asthma connection: A link in the innate immune system?

asthmatic airway
Obesity may set off innate immune factors that inflame the lungs.

Both asthma and obesity have surged in recent decades, and a growing body of literature is linking the two conditions. Various explanations have been proposed: One recent study suggests that hormonal factors in obesity may regulate airway diameter; another suggests that obesity activates asthma-related genes.

“Why obesity predisposes a person to asthma has been a real puzzle,” says Dale Umetsu, MD, PhD, who recently researched the problem with Hye Young Kim, PhD, and other colleagues in the Division of Allergy and Immunology at Boston Children’s Hospital. “Our goal was to find the connection between these two problems, which occur in both children and adults, and to explore possible new treatments.”

The team’s research indicates that obesity alters the innate immune system—the body’s first responder to infection—in several ways, resulting in lung inflammation. Published earlier this month in Nature Medicine, their work also suggests a completely new, “druggable” approach to treating patients with obesity-associated asthma, for whom standard asthma drugs often work poorly.

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Zebrafish plus iPS cells make a drug discovery platform with muscle

Cell cover about using zebrafish and iPS cells to find muscle-building drugs.
In a one-two-three punch, a rapid screen in zebrafish can quickly identify a short list of drug candidates to test in mice and in patient-derived cells.

Scientists have had little success in growing skeletal muscle for patients with muscular dystrophy and other disorders that degrade and weaken muscle. Undertaking experiments in zebrafish, mouse and human cells, researchers have identified a way to do that, creating cells that Leonard Zon, MD, hopes to see tested in patients in the next several years.

But what really excites Zon, director of the Stem Cell research program at Boston Children’s Hospital, is the power of the chemical screening platform he and his colleagues used. Described last week in the journal Cell, it found a cocktail of three compounds that induced human muscle cells to grow—in just a matter of weeks. Zon believes it could fast-track drug discovery for multiple disorders.

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The ever-changing, interwoven regulatory and drug-pricing landscape

Tangled roots
Drug approval is increasingly intertwined with pricing questions.

At last month’s BioPharm America conference, what I originally thought would be a run-of-the-mill panel wound up being a frank discussion about regulatory and pricing challenges that pharma and biotech companies are facing today. I hadn’t realized these two challenges are intertwined so closely.

The regulatory and pricing paths for new drugs in the United States have become increasingly difficult to navigate. Due to outside policy pressures, the FDA is scrutinizing drugs more than in the past, requiring much more data. Even when a drug is approved, there is no guarantee that payers will cover its full cost, as they are starting to consider the drug’s overall value—improving quality of life and decreasing costs—along with its effectiveness.

Meanwhile, in many European single-payer countries, pharmaceutical companies are being told how to price their drugs before they are considered for approval by the regulatory agencies. The likely effect is less return on investment on new drugs, which could in turn decrease the pace of innovation.

Vaughn Kailian, managing director of MPM Capital, a health care venture capital investment firm, led an eye-opening conversation around these topics.

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