Four Distinct Subtypes of Gastric Cancer Found


The study also found higher levels of the JAK2 gene in patients with the EBV-positive subtype, suggesting that certain gastric cancers could be susceptible to JAK2 inhibitors, such as ruxolitinib. However, at this point, studies are not currently examining JAK2 inhibition in this disease type. An earlier study did explore AZD1480 with gastric cancer; however, development of this compound was discontinued.

Amplifications in PD-L1/2 in the EBV-positive subtype indicate that checkpoint inhibitors directed toward these ligands could be effective. A phase I study is investigating the PD-L1 inhibitor MPDL3280A in patients with solid tumors or hematologic malignancies. Patients with gastric cancer will be enrolled in this study, although it is not specifically looking for the EBV-positive subtype. The chromosomally unstable category represented the largest subtype, with these tumors generally being located in the areas between the stomach and esophagus. Bass noted that these tumors have a striking number of genomic amplifications of key cancer-promoting genes.
This finding result opens up an entirely new line of research to allow us to investigate what underlies this deadly form of gastric cancer and to ultimately develop new therapies. The NCI and the National Human Genome Research Institute, which are run by the National Institutes of Health (NIH), manages TCGA. In a press release concerning the results, the director of the NIH characterized the EBV findings as groundbreaking.

This study reinforces the value of the approach we are using to study genomic diversity and similarity among tumors of many different cancer types. Only such a systematic analysis could have yielded observations about the association between EBV and several provocative molecular characteristics.

Four Distinct Subtypes of Gastric Cancer Found

According to a paper published in Nature by The Cancer Genome Atlas (TCGA), gastric cancer is comprised of 4 distinct molecular subtypes of disease, each representing a unique opportunity for new drug development.

The study evaluated the molecular composition of 295 primary gastric adenocarcinomas using 6 different molecular analysis platforms that utilized DNA and RNA sequencing and protein arrays. The 4 main subtypes that emerged in the study were Epstein–Barr virus (EBV)-positive, microsatellite unstable, genomically stable, and chromosomal instable. Within each of these subtypes, the study identified distinct molecular targets for future drug development, including PD-L1 and PD-L2 amplification in EBV-positive tumors. Moreover, tumors with chromosomal instability expressed amplification of tyrosine kinase receptors.

A key advance with this project identified and developed a much more useful classification system to find groups of gastric cancer. At the same time, we also identified key targets to pursue in different groups of patients,” lead investigator Adam Bass, MD, from the Harvard Medical School and Dana-Farber Cancer Institute. This will provide a strong foundation for categorizing the disease and for doing so in a way in which we can develop clinical trials based on some of the critical molecular alterations that are driving different classes of cancers.

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In July, the PI3K delta inhibitor idelalisib gained approval in combination with rituximab as a treatment for patients with chronic lymphocytic leukemia. Additionally, several other PI3K inhibitors are in development. A phase I study exploring the investigational PI3K inhibitor BYL719 in combination with the Hsp90 inhibitor AUY922 is currently enrolling patients with metastatic gastric cancer.

Gilead’s oncology contender comes up short in pancreatic cancer

Simtuzumab is an antibody that blocks the LOXL2 enzyme, which is believed to play a major role in tumor progression and fibrosis. To test its mettle in pancreatic cancer, Gilead enrolled 236 treatment-naive patients, dosing half with a combination of simtuzumab and chemotherapy. After 28 weeks, simtuzumab proved no better than placebo at forestalling tumor progression, flunking its primary endpoint.

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But simtuzumab, as the pancreatic study was just one of 5 ongoing Phase II trials on the drug. Although simtuzumab did not provide clinical benefit in difficult-to-treat advanced pancreatic cancer patients in this study, continue to explore simtuzumab in other areas of unmet medical need, with ongoing clinical trials in colorectal cancer, myelofibrosis, and serious fibrotic lung and liver diseases.

Analysts say those last two indications may be the drug’s best bets. On the lung disease side, Gilead is studying simtuzumab in idiopathic pulmonary fibrosis (IPF), a rare ailment with no approved treatments and potential market that helped convince Roche to pay $8.3 billion for InterMune. And the drug’s targeted indication in liver disease is fibosis caused by non-alcoholic steatohepatitis (NASH), another unmet medical need that has jump-started the shares of Intercept Pharmaceuticals’, a leader in the space.

The Phase II misstep is a blow for Gilead’s on-the-come-up cancer department, which has largely been pieced together through M&A over the past three years. Idelalisib, a blood cancer treatment approved in July as Zydelig, came through the company’s $600 million deal for Calistoga Pharmaceuticals in 2011, while momelotinib, a Phase III myelofibrosis drug, was the target of Gilead’s $510 million buyout of YM Biosciences a year later. Rounding out the oncology pipeline is GS-9973, which targets blood malignancies, and GS-5745, designed to combat solid tumors.

PI3K Inhibitor Combinations in Breast Cancer part2


In the LEE011 plus letrozole arm, there was 1 confirmed partial response in a patient who received prior treatment with letrozole, fulvestrant, and a PI3K inhibitor for advanced/metastatic disease. Additionally, 3 patients had stable disease and 5 had neither complete response nor progressive disease (NCRNPD). In patients treated with BYL719 plus letrozole, 3 had stable disease and 3 had NCRNPD.

The phase II dose of LEE011 was declared to be 600 mg/day. In arm 2, only 9 of the 12 patients were evaluable for dose-determining decisions, and no dose-limiting toxicities occurred. The phase II dose of BYL719 was determined to be 300 mg/day.The most common adverse events (all grade) in LEE011 recipients were neutropenia (85%), leucopenia (39%), nausea (39%), anemia (23%), fatigue (23%), and lymphopenia (23%). Grade 3/4 adverse events suspected to be drug-related were neutropenia (46%), leucopenia (15%), and lymphopenia (23%).

In BYL719 recipients, diarrhea (50%), nausea (42%), and hyperglycemia (42%) were the most common adverse events, and the grade 3/4 adverse events suspected to be drug-related were hyperglycemia (17%), fatigue (8%), hyponatremia (8%), lymphopenia (8%), rash (8%), and morbilliform (8%). BYL719 had demonstrated activity in HR-positive breast cancer as a single agent and in combination with letrozole in preclinical mouse models. Additionally, LEE011 demonstrated early signs of single-agent clinical activity in advanced solid tumors. The phase Ib/II study sought to explore LEE011, BYL719, and letrozole. The maximum tolerated dose discovered in the dose-escalation portion of the study will be utilized in the phase II expansion study.

The evidence of feasibility of combining LEE011 and letrozole has led to the design of a phase III study for postmenopausal women with HR-positive, HER2-negative disease who have not received prior therapy. In this study, patients will be randomized to LEE011 and letrozole or placebo plus letrozole, with progression-free survival as the primary endpoint. This study, labeled MONALEESA-2, is currently recruiting patients (NCT01958021).

PI3K Inhibitor Combinations in Breast Cancer part1


The combination of letrozole with either the CDK4/6 inhibitor LEE011 or the PI3 kinase Inhibitor BYL719 demonstrated clinical activity for women with ER-positive, HER2-negative breast cancer, according phase Ib data presentation by Pamela N. Munster, MD, at the 2014 Breast Cancer Symposium.

In the phase Ib portion of the study, patients received treatment with LEE011 and BYL719 at various doses in a 28-day cycle. Letrozole was administered at 2.5 mg per day. LEE011 was administered for 21 days followed by a 7-day break, and BYL719 was administered daily. The goal of the analysis was to find a maximum tolerated dose, at which point the study would enroll patients with metastatic disease who had not received a prior systemic therapy other than letrozole into a dose expansion cohort. This randomized phase II portion of the study will compare letrozole, LEE011, and BYL719 to letrozole plus either LEE011 or BYL719.

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PI3 kinase is activated in many cancers. The CDK4/6 -Rb pathway is crucial to many cancers. In estrogen receptor-positive tumors, that pathway is particularly vulnerable to inhibition. In the dose escalation portion of the study, patients received several prior lines of endocrine therapy and up to one prior cytotoxic regimen in the metastatic or locally advanced setting. All patients had ER-positive, HER2-negative breast cancer. Results were available for 13 patients treated with LEE011 and letrozoleand 12 treated with BYL719 and letrozole.

New drug combination targets for Lung cancer


Last week in Nature Medicine, a study led by Christine, assistant professor of Medicine and Cancer Biology, was published online. The work was based on an intriguing clinical observation of a female patient with advanced lung cancer who had an unexpected response to a monoclonal antibody that targets the insulin-like growth factor receptor (IGF-1R). IGF-1R helps cancer cells survive and evade anti-cancer therapies.

Remarkably, the patient remained on the IGF-1R therapy for 17 months — far longer than any other patient on the clinical trial. The researchers became interested in why this particular patient’s tumor responded to the experimental therapy so dramatically. Investigators decided to test for gene mutations and found an unexpected result — the patient’s tumor was positive for an ALK gene fusion. Only about 5 percent of lung cancer patients have this gene fusion in their tumor.

With this new information, the patient was enrolled in another clinical trial testing crizotinib, a drug that targets ALK rearrangements, and her cancer stopped progressing for several more months. This patient’s surprising response to different forms of therapy sparked a new line of research to identify and explain the biological mechanisms at work. Researchers from medical centers in the United States, Germany and Australia tested the ability of IGF-1R inhibitor therapies alone or in combination with ALK inhibitors to impede the growth of ALK+ lung cancer and to overcome acquired resistance to ALK inhibitor therapies.

Working in cell lines, mouse models and patient lung tumor cells, they tested the two types of drugs and found that the combination therapy enhanced the ability to slow down the growth of ALK+ lung cancer cells. They found similar results in cell lines from ALK+ lymphoma, a different form of cancer harboring the same tumor genetic alteration.

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Pfizer and Merck Collaborate on ALK-Positive NSCLC


Crizotinib  is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC)  Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells. Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors. Pembrolizumab (also known as MK-3475) is a drug in marketted by Merck that targets the programmed cell death 1 (PD-1) receptor. The drug is intended for use in treating metastatic melanoma.

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Pfizer and Merck announced that they have entered into an agreement to explore the therapeutic potential of the combination of Pfizer’s crizotinib  with Merck’s investigational anti-PD-1 antibody pembrolizumab. A clinical study evaluate the safety and tolerability of the combination in patients with ALK-positive advanced or metastatic non-small cell lung cancer (NSCLC). This collaboration between Pfizer and Merck is just one example of the willingness of sponsors to work together in an effort to accelerate progress against some of the most difficult-to-treat cancers. The effects of combining one drug, crizotinib, which inhibits an abnormally activated enzyme in patients with ALK-positive metastatic lung cancer, with the investigational drug, pembrolizumab, which harnesses the body’s immune system to fight cancer.

This multi-center, open-label clinical study is expected to begin in 2015. Pfizer will conduct the study. Both companies previously announced plans to evaluate the safety and efficacy of pembrolizumab in combination with Pfizer’s small molecule kinase inhibitor axitinib in patients with renal cell carcinoma. Separately, pembrolizumab plus Pfizer’s PF-05082566 (PF-2566), an investigational immuno-oncology agent that targets the human 4-1BB receptor, will be evaluated in multiple cancer types. These studies are expected to begin enrollment later this year.

 

DP1 suppression, a relevant therapeutic strategy in ALS

Researchers from Harvard University announced last week they may have found an ALS therapy. When they blocked the gene for prostanoid receptor DP1 in ALS-model glial cells in a dish, they found neurons made from human embryonic stem (ES) cells were protected from death.

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When they created ALS (amyotrophic lateral sclerosis) mice with that same gene deleted, the mice lived 6.7 percent longer. This finding helps validate the idea that neurons made from human stem cells. The 6.7 percent survival increase may rise even more, if/when their DP1 antagonist is given with a drug they earlier found has anti-ALS properties.

In Science Translational Medicine, the Eggan team reported creating motor neurons from green fluorescent protein (GFP)-expressing ES cells. These were then co-cultured with either normal cells, or SOD1 mutant glial cells, from neonatal mice. (SOD-1 is a gene mutated in a subset of ALS patients.) After ten days, they found the glial cells from the SOD1 mice caused a 55 percent decrease in motor neurons— compared to neurons co-cultured with normal glial cells.

the DP1 receptor is a critical mediator of glial toxicity to motor neurons in a stem cell model of ALS. Elimination of even a single allele of the gene encoding this receptor significantly extended the life span of the most widely studied ALS mouse model. Inhibition of the DP1 receptor is a rational strategy for slowing the negative impact of microgliosis in ALS.

Chronic treatment with a selective DP1 antagonist protected the neurons from toxic SOD1 glia, the team reported. The team then found an activator of DP1 caused a 49 percent decrease in motor neurons, similar to the effect of SOD1 mutant glia. The team also found the DP1 inhibitor acted on glial cells, which then impacted neurons. it is still unclear to what extent findings from stem cell models will be predictive of outcomes in vivo, this provides in vivo validation that DP1 suppression is a relevant therapeutic strategy in ALS.

A family of proteins block the release of HIV and other viruses

University of Missouri researchers have found that a family of proteins that promotes virus entry into cells also has the ability to block the release of HIV and other viruses. The study was published in the Proceedings of the National Academy of Sciences. It’s a surprising finding that provides new insights into our understanding of not only HIV infection, but also that of Ebola and other viruses.

AIDS, which caused by the human immunodeficiency virus type 1 (HIV-1), is a condition characterized by progressive failure of the immune system. Today, more than one million Americans currently are living with AIDS. When HIV or any virus infects a cell, it replicates and spreads to other cells. One type of cellular protein— T cell immunoglobulin and mucin domain(TIM-1)— has previously been shown to promote entry of some highly pathogenic viruses into host cells. Now, the researchers have found that the same protein possesses a unique ability to block the release of HIV-1 and Ebola virus.

This study shows that TIM proteins keep viral particles from being released by the infected cell and instead keep them tethered to the cell surface. Scientists performed a series of experiments that revealed the protein’s ability to inhibit HIV-1 release, resulting in diminished viral production and replication.

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White blood cells, such as T cells ,play an important role in the body’s response to infection, but HIV-1 disrupts the cells’ ability to fight back against infection. When the virus enters a host cell, it infects the cell and replicates, producing viral particles that spread to and infect other cells. The researchers found that as the viral particles attempt to bud from, or leave, the infected cell, the TIM-family proteins located on the surface of the cell can attach to lipids on the surface of the viral particle.

These lipids–phosphatidylserine (PS)— are normally present on the inner side of the cellular membrane but can be exposed to the outer side upon viral infection. When the TIM-family proteins come in contact with PS, the viral particle becomes attached to the host cell, keeping the particle from being released from the cell. Because TIM-family proteins and PS are present on the surface of the cell and the viral particle, the viral particles get stuck to one another, forming a network of viral particles that accumulate on the surface of the host cell, rather than being released to infect other cells.

By using molecular, biochemical and electron microscopic approaches, the researchers observed the TIM and PS interactions in human cells. The next step is for the researchers to study the biological significance of TIM-family proteins in animals and patients and to determine the fate of the infected cell once it accumulates a buildup of viral particles. This discovery furthers our ultimate goal of understanding the biology of TIM-family proteins and potentially developing applications for future antivirus therapies.

Reference:http://www.pnas.org/content/early/2014/08/14/1404851111.abstract