Category Archives: Gene Medicine

Two gene editing firms unveil cancer drug pacts as ASCO comes to a close Boston Business Journal The research drew blowback from Intellia, which said that the claim about off-target effects lacked evidence and was based on a sample. In addition to Intellia and CRISPR Therapeutics, the other leading gene-editing firm is Cambridge-based Editas ... and more »

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Two gene editing firms unveil cancer drug pacts as ASCO comes to a close - Boston Business Journal

An experimental cancer medicine called larotrectinib has shown promise in treating a diverse range of cancers in people young and old, researchers said at a major cancer conference in the United States.

The treatment targets a genetic abnormality which is often found in rare cancers including salivary gland cancer, juvenile breast cancer, and a soft tissue cancer known as infantile fibrosarcoma which are particularly difficult to treat. This abnormality also occurs in about 0.5% to 1% of many common cancers.

In the study released at the American Society of Clinical Oncology conference, 76% of cancer patients both children and adults with 17 different kinds of cancer responded well to the medicine.

A total of 79% were alive after one year. The study is ongoing. And 12% went into complete remission from their cancer.

The clinical trial included 55 patients 43 adults and 12 children. All had advanced cancers in various organs, including the colon, pancreas and lung, as well as melanoma.

These findings embody the original promise of precision oncology: treating a patient based on the type of mutation, regardless of where the cancer originated, said lead study author David Hyman, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York.

We believe that the dramatic response of tumours with TRK fusions to larotrectinib supports widespread genetic testing in patients with advanced cancer to see if they have this abnormality.

Researchers said 76% of cancer patients both children and adults with 17 different kinds of cancer responded well to the medicine. (Shutterstock)

Made by Loxo Oncology Inc., larotrectinib is a selective inhibitor of tropomyosin receptor kinase (TRK) fusion proteins. TRK proteins are a product of a genetic abnormality when a TRK gene in a cancer cell fuses with one of many other genes, researchers said.

The US Food and Drug Administration has not yet approved the treatment for widespread use.

The treatment was well tolerated by patients, and the most common side effects were fatigue and mild dizziness.

If approved, larotrectinib could become the first therapy of any kind to be developed and approved simultaneously in adults and children, and the first targeted therapy to be indicated for a molecular definition of cancer that spans all traditionally-defined types of tumors. said Hyman.

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New cancer medicine targets rare genetic flaw, finds study - Hindustan Times

The founding mission of MIT may seem like an unusual meal-time story for a child. But when Mark Bathe was growing up, it was a regular topic of conversation around the dinner table.

That is because Bathes father, mechanical engineer Klaus-Jrgen Bathe, was a long-standing, proud MIT faculty member, and regularly talked about MIT founder William Barton Rogers mission for the Institute.

Bathes father was a huge presence in his childhood, and his enthusiastic descriptions of MITs focus on fundamental yet hands-on science to benefit society made quite an impression on him. My father was the lens through which I saw the world, Bathe says.

So when Bathe was admitted to both MIT and another university as a senior in high school, there was little doubt in his mind as to where he would be enrolling.

Bathe joined MITs Department of Mechanical Engineering as an undergraduate, where he considers himself fortunate to have been trained in a broad and fundamental, yet problem-oriented, manner.

But with a longstanding desire to impact human health through medicine, Bathe moved on to graduate research in biomechanical engineering, in part under the stewardship of Alan Grodzinsky, a professor of biological, mechanical, and electrical engineering, and director of the MIT Center for Biomedical Engineering.

After receiving his PhD in 2004, Bathe decided to deepen his understanding of biomolecules by moving to the University of Munich in 2006, to carry out postdoctoral research in biological physics.

He then returned to MIT in 2009, joining the Department of Biological Engineering, where he established an interdisciplinary research group focused on using approaches from engineering, chemistry, physics, and computer science to understand and solve problems in applied biology.

I find the new emerging world of personalized medicine fascinating, Bathe says. In particular, the prospect of using gene-editing tools to correct disease-causing mutations that are either inherited or acquired, as well as the use of messenger RNAs to express specific proteins that are needed to alleviate disease.

Bathe, now an associate professor of biological engineering at MIT, creates a huge variety of programmed three-dimensional shapes out of single strands of synthetic DNA, a process known as DNA origami. These nanoparticles may ultimately be deployed as structural scaffolds to deliver vaccines, drugs, or even gene-editing tools such as CRISPR-Cas9 to specific parts of the body, he says.

Once delivered, the therapeutic payload could be released to edit the faulty genes that cause certain diseases.

It amazes me that with two therapeutic tools, namely CRISPR for gene editing and therapeutic messenger RNAs for protein production, we could, in principle, cure nearly any disease, potentially with minimal side-effects, but only if we can figure out how to successfully deliver these tools to act highly specifically in the target cells of interest, such as the gut, lungs, brain, or other organs, he says.

Tackling this problem can only be achieved through an interdisciplinary, long-term research effort, he believes.

Targeted therapeutic delivery is a highly interdisciplinary problem, involving everything from very applied, clinical medicine to basic macromolecular chemistry of nucleic acids and proteins, as well as the physics and engineering of macromolecular transport, Bathe says.

As a starting point, his laboratory, which includes engineers, chemists, computer scientists, and physicists, developed DAEDALUS (DNA Origami Sequence Design Algorithm for User-defined Structures), an algorithm designed to automate the process of assembling DNA nanoparticles. DAEDALUS, which takes a simple 3-D representation of the object and determines how this should be assembled from the DNA strands, can build any type of enclosed 3-D shape.

As a result, the algorithm, combined with new nucleic acid synthesis procedures, which were published in a paper in the journal Science last year, are allowing Bathe and his team to build the nanoparticles far more quickly and easily than was previously possible.

Despite decades of research into the delivery of nucleic acids and proteins, and the considerable potential for these therapeutics in clinical medicine, little progress has been made as measured by FDA-approved therapies, says Bathe. This is likely due in part to our poor understanding of macromolecular transport in the complex human anatomy, but also due to the lack of techniques available to engineer delivery tools, he says.

Were hopeful that fully synthetic, viral-like nucleic acid nanoparticles developed in our lab offer a new opportunity for the rational engineering of delivery tools for gene-centric therapies, he explains.

Working with with the Stanley Center for Psychiatric Research, Bathe and his team are also investigating novel methods of imaging patient-derived neuronal cells, in a bid to better understand how genes affect the signals sent between individual neurons in the brain.

He is also investigating the use of DNA and other molecules to store and process information, with density that is orders of magnitude higher than conventional silicon-based computing hardware.

When not in the classroom or his laboratory, Bathe takes part in a range of outdoor activities, including cycling, running, skiing, and hiking, as well as indoor swimming with MITs Masters Swim Team. He also greatly enjoys an occasional sprint triathlon on summer weekends.

My favorite weekend in the Boston area, however, is a ferry ride down to Marthas Vineyard for a bike ride around the island, ending with a swim and lobster roll by the seaside in Edgartown, he says. I cant recommend it highly enough!

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Deploying therapeutic payloads to cells - MIT News

SUNDAY, June 4, 2017 (HealthDay News) -- A twice-daily pill could help some advanced breast cancer patients avoid or delay follow-up sessions of chemotherapy, a new clinical trial reports.

The drug olaparib (Lynparza) reduced the chances of cancer progression by about 42 percent in women with breast cancer linked to BRCA1 and BRCA2 gene mutations, according to the study.

Olaparib delayed cancer progression by about three months. The drug also caused tumors to shrink in three out of five patients who received the medication, the researchers reported.

"Clearly the drug was more effective than traditional chemotherapy," said Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society.

"This is a group where a response is more difficult to obtain -- a young group with a more aggressive form of cancer -- and nonetheless we saw a close to 60 percent objective response rate," he said.

The study was funded by AstraZeneca, the maker of Lynparza.

Olaparib works by cutting off the avenues that malignant cancer cells use to stay alive, said lead researcher Dr. Mark Robson. He's a medical oncologist and clinic director of Clinical Genetics Service at Memorial Sloan Kettering Cancer Center in New York City.

The drug inhibits PARP, an enzyme that helps cells repair damaged DNA, Robson said.

Normal cells denied access to PARP will turn to the BRCA genes for help, since they also support the repair of damaged DNA, Robson said.

But that "backup capability" is not available to breast cancer cells in women with BRCA gene mutations, Robson said.

"When you inhibit PARP, the cell can't rescue itself," Robson said. "In theory, you should have a very targeted approach, one specifically directed at the cancers in people who have this particular inherited predisposition."

Olaparib already has been approved by the U.S. Food and Drug Administration for use in women with BRCA-related ovarian cancer. Robson and his colleagues figured that it also should be helpful in treating women with breast cancer linked to this genetic mutation.

The study included 302 patients who had breast cancer that had spread to other areas of their body (metastatic breast cancer). All of the women had an inherited BRCA mutation.

They were randomly assigned to either take olaparib twice a day or receive standard chemotherapy. All of the patients had received as many as two prior rounds of chemotherapy for their breast cancer. Women who had hormone receptor-positive cancer also had been given hormone therapy.

After 14 months of treatment, on average, people taking olaparib had a 42 percent lower risk of having their cancer progress compared with those who received another round of chemotherapy, Robson said.

The average time of cancer progression was about seven months with olaparib compared with 4.2 months with chemotherapy.

Tumors also shrank in about 60 percent of patients given olaparib. That compared with a 29 percent reduction for those on chemotherapy, the researchers said.

Severe side effects also were less common with olaparib. The drug's side effects bothered 37 percent of patients compared with half of those on chemo. The drug's most common side effects were nausea and anemia.

"There were fewer patients who discontinued treatment because of toxicity compared to those who received chemotherapy," Robson said. "Generally it was pretty well tolerated."

Only about 3 percent of breast cancers occur in people with BRCA1 and BRCA2 mutations, the researchers said in background notes.

Despite this, the results are "quite exciting," said Dr. Julie Fasano, an assistant professor of hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York City.

Olaparib could wind up being used early in the treatment of metastatic breast cancer as an alternative to chemotherapy, and future studies might find that the drug is effective against other forms of breast cancer, Fasano said.

"It may be a practice-changing study, in terms of being able to postpone IV chemotherapy and its associated side effects" like hair loss and low white blood cell counts, Fasano said.

Lichtenfeld noted that olaparib also places less burden on patients.

"It may be easier for women to take two pills a day rather than go in for regular chemotherapy," Lichtenfeld said. "Clearly, this is a treatment that will garner considerable interest.

The findings were scheduled to be presented Sunday at the American Society of Clinical Oncology's annual meeting, in Chicago. The study was also published June 4 in the New England Journal of Medicine.

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Drug Helps Fight Breast Tumors Tied to 'Cancer Genes' - The Tand D.com

CHICAGOWhen Merck & Co.s Keytruda won approval last week to treat tumors based on a common biomarkerrather than the location in the body where the tumor originated, talk was thatthe true start of precision medicine had arrived.

The $1.3 billion market cap biotech Loxo Oncology is hoping to be a part of that journey. At the American Society of Clinical Oncology meeting Saturday, Loxo posted the latest data for its experimental larotrectinib (LOXO-101), amedicationit hopes will treat an array of cancers innearly a dozen sites across the body.

The data showed that 50 larotrectinib patients withtumors harboring tropomyosin receptor kinase (TRK) fusions had a 76% objective response rate (ORR) across tumor types. The drug met its primary endpoint; key secondary endpoints, including progression-free survival and duration of response, had not yet been reached.

The data drewfrom three trials, a phase 1 study in adults, a phase 2 study called Navigate, and a phase 1/2 pediatric trial called Scout.The results were based on the intention-to-treat principle, using the first 55 TRK fusion patients enrolled to the three trials, regardless of their prior therapy or tumor-tissue diagnostic method.

In all, 44 adults and 12 younger patients were enrolled, with tumors identified by 14 different lab tests. The TRK fusion patients carried a host of primary diagnoses, including appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal stromal tumor, infantile fibrosarcoma, lung cancer and more.

The confirmed overall response rate was 76% in 50 patients, with these rates generally consistent across tumor types, TRK gene fusions, and various diagnostic tests, Loxo said in a statement.

In the pediatric setting, larotrectinib also showed promising activity in the presurgical management of patients with infantile fibrosarcoma, with three patients treated to best response.

The drug, developed in partnership with Array Biopharma,has a breakthrough designation from the FDA to treat children and adults with metastatic or inoperable solid tumors that test positive for the TRK biomarker, and who've either failed on previous treatments or have no acceptable alternatives.

In the safety department, Loxo says that seven(13%) of the study patients had their doses reduced because of side effects, but no patients stopped taking larotrectinib after suffering side effects.

All patients whose doses were lowered experienced tumor regression, which then continued on the reduced dose. Nearly all of the dose reductions were due to infrequent neurocognitive adverse events, likely a result of on-target TRK inhibition in the [central nervous system], Loxo explained.

Loxo added that sixpatients responded to larotrectinib but later progressed, a pattern referred to as acquired resistance.

The company is gathering other evidence forlarotrectinib'sapplication for FDA approval, slated for late this year or early next. Acentral, independent radiology review will be performed in the second half of 2017, and Loxo plans to announce that data before the end of the year. A separate assessment by independent radiologists, not yet conducted, will also be required to support its regulatory filing, the companynotes.

TRK is a neuron-stimulating factor that is active in fetal development but has its expression switched off later in life. In some cases, the TRK gene can fuse with other genes and reactivate, causing various forms of cancer.

Loxo's development program for the drug is agnostic to any particular tumor type, focusing instead on recruiting patients whose cancer cells express the TRK gene. If approved, the drug could be prescribed across multiple solid tumor types on the strength of genetic testing for neurotrophic TRK (NTRK) fusion proteins, which it will do with the help of Roche.

RELATED: Merck's Keytruda wins first FDA nod to treat genetically ID'd tumors anywhere in the body

NTRK mutations crop up in a small percentage of patients with any particular cancer, but they add up. The company estimated last year that between 1,500 and 5,000 late-stage cancer patients could be eligible for treatmentin the U.S. each year, with a similar number in Europe.

[T]he larotrectinib TRK fusion story fulfills the promise of precision medicine, where tumor genetics rather than tumor site of origin define the treatment approach," said David Hyman, lead investigator in the Navigate trial and chief of the early drug development service at Memorial Sloan Kettering Cancer Center."It is now incumbent upon the clinical oncology and pathology communities to examine our testing paradigms, so that TRK fusions and other actionable biomarkers become part of the standard patient workup."

The company also has two follow-up candidatesLOXO-292 and LOXO-195which target other cancer-causing genes resulting from fusions with kinase genes.

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Prepping for FDA filing, Loxo rolls up data on its site-agnostic cancer med larotrectinib - FierceBiotech

June 2, 2017 Credit: CC0 Public Domain

A study at The University of Texas MD Anderson Cancer Center has shown promise for effective treatment of therapy-resistant cancers caused by a mutation of the RAS gene found in many cancers. The pre-clinical study combined therapies targeting the inhibitors polyADP ribose polymerase (PARP) and mitogen-activated protein kinase (MEK). The findings were published this week in Science Translational Medicine.

Mutations in the RAS gene account for more than 90 percent of pancreatic cancers, 50 percent of colorectal cancers, and 30 percent of lung cancers, and a significant portion of many other types of tumors. Unfortunately, these cancers are usually resistant to traditional treatments contributing to poor patient outcomes.

"Nowhere is the need for targeted therapies greater than for cancers driven by oncogenic RAS, which represents the most common type of potentially targetable mutation in cancer," said Gordon Mills, M.D., Ph.D., chair of Systems Biology. "Our study demonstrated that the rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS-mutant tumors where there are few effective therapeutic options."

PARP inhibitors block a key pathway for cellular DNA repair, effectively stopping many cancers with defects in DNA repair from growing, but the disease soon gains resistance due to the tumor's cell ability to adapt to stresses caused by the therapy. MEK inhibitors also are used to affect pathways often overactive in some cancers.

Mills' team found that combinations of PARP and MEK inhibitors evoked "unexpected cytotoxic effects" in vitro and in vivo in multiple RAS-mutant tumor models across tumor lineages where RAS mutations are prevalent. The combination therapy worked independent of mutations in tumor suppressor genes including BRCA1, BRCA2 and p53, suggesting the dual therapy's potential as a treatment for multiple RAS-mutant cancers. It also was effective for tumors that had become resistant to PARP, as well as in cells that did not have aberrations in BRCA1 and BRCA2, suggesting the combination could expand to a wide spectrum of patients likely to benefit.

"The sensitivity of RAS-mutant cells to the combination appears to be independent of intrinsic gene expression patterns, as observed across multiple different lineages," said Mills. "Because the synergistic responses to MEK1 and PARP1 combinations also were independent of p53 mutation status, the approach should be effective in both normal and mutant p53 tumors. Together, the in vitro and in vivo data argue that a MEK1 and PARP1combination offer the potential to induce cell death and increase the magnitude, duration and spectrum of PARP activity."

Currently, clinical trials in this area of investigation are under consideration at MD Anderson.

Explore further: New findings may enhance PARP inhibitors therapy in breast cancer

More information: C. Sun el al., "Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers," Science Translational Medicine (2017). stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aal5148

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Combination therapy targets genetic mutation found in many cancers - Medical Xpress