Epigenomic changes play an important role during the progression of melanoma

Human DNA contains genetic information that makes our cells functional entities within a larger whole. The stream of information from DNA to function happens in the form of proteins that anchor themselves to various locations in the DNA and transcribe genetic information into functional cell parts. This process is strictly regulated and is thus very sensitive to change by external factors.

Such changes, called gene-regulatory or epigenomic changes, can alter the regular stream of information between the DNA and the cell without actually altering the DNA itself.

In their study, Professor Stein Aerts (KU Leuven) and Professor Chris Marine (VIB/KU Leuven) were able to confirm that epigenomic changes play an important role in the development and progression of melanoma.

Previous research has shown that melanomas are made up of various types of cells. Each subpopulation of cells in the tumour has different characteristics. What makes melanoma so aggressive, say the researchers, is the existence of a subpopulation that causes progression and metastasis of the cancer. These cells also increase the resistance of the tumour to current cancer drugs.

The researchers found that these subpopulations do not arise from mutations or errors in the DNA itself but are the result of changes in the stream of information from the DNA to the cell. In a first phase of cancer, specific proteins bind themselves to specific locations in the DNA, which allow the tumour to grow. In a second, more aggressive phase, other proteins are activated that bind to other DNA sites, which allow the cancer cells to invade and spread to other tissues in the body.

Professor Aerts and his team succeeded in mapping the epigenomic landscape in both phases of melanoma progression. They identified the proteins and the thousands of regions on the DNA to which the proteins bound themselves. Furthermore, when the researchers knocked out these proteins, the melanoma became much less aggressive and more receptive to existing cancer drugs.

This is the first complete epigenomic profile of melanoma and the first study to map the regulatory landscape of the different melanoma cell states.

The results contribute to a more complete picture of cancer cells during melanoma progression and constitute an important step forward in the search for more targeted, more effective therapies for this aggressive type of cancer.

source : http://www.sciencedaily.com/releases/2015/04/150409102106.htm

Axillary lymph node evaluation performed frequently in ductal carcinoma in situ

While axillary lymph node evaluation is the standard of care in the surgical management of invasive breast cancer, a benefit has not been demonstrated in ductal carcinoma in situ (DCIS). For women with invasive breast cancer, sentinel lymph node biopsy (SLNB) replaced full axillary lymph node dissection (ALND). The sentinel nodes are the first few lymph nodes into which a tumor drains.

Guidelines published by the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend against axillary evaluation in women undergoing breast-conserving surgery (BCS). If invasive cancer were to be discovered SLNB could be performed at a later date. But because a total mastectomy precludes future SLNB, the guidelines suggest SLNB may be appropriate for some high-risk patients because axillary evaluation would be indicated if invasive cancer was found, according to background in the study.

Dawn L. Hershman, M.D., M.S., of Columbia University Medical Center, New York, and coauthors determined the incidence of axillary lymph node evaluation in women with DCIS and identified factors associated with the procedure. The authors analyzed medical records from 2006 through 2012 for women with DCIS who had BCS or mastectomy. The study analysis included 35,591 women.

Of the women with DCIS, 26,580 (74.7 percent) had BCS and 9,011 (25.3 percent) underwent mastectomy. The authors found that 17.7 percent of the women who had BCS and 63 percent of those patients who underwent mastectomy had an axillary lymph node evaluation, according to the results. Among the 63 percent of women who had a mastectomy and underwent axillary evaluation, 15.2 percent of women had full ALND and 47.8 percent had SLNB. Among the 17.7 percent of women who had axillary evaluation with BCS, 16.7 percent of women underwent SLNB and only 1 percent had ALND.

Rates of axillary evaluation increased over time with mastectomy from 56.6 percent in 2006 to 67.4 percent in 2012, but the rates remained relatively stable with BCS with 18.5 percent in 2006 and 16.2 percent in 2012.

Factors such as having surgery at a nonteaching hospital in an urban area were associated with higher rates of axillary evaluation with mastectomy and increasing surgeon volume was associated with decreasing axillary evaluation among women undergoing BCS, the results also indicate.

“Despite uncertainty regarding the clinical benefit of axillary evaluation in women with DCIS, we found that 17.7 percent of women undergoing BCS and 63 percent of women undergoing mastectomy had either an SLNB or ALND. Though use of axillary evaluation in DCIS may be appropriate in some cases, the high rates of axillary evaluation indicate that additional research is needed in this area. In addition to better predictive tools for axillary involvement, other surgical approaches should be evaluated, such as placing a marker in the node rather than removing it, thus allowing for sentinel node removal at a second operation should invasive cancer be identified on final pathology. Perhaps most importantly, additional prospective evaluation is needed to determine if there is a clinical benefit to axillary evaluation in women with DCIS,” the study concludes.

source : http://www.sciencedaily.com/releases/2015/04/150409120257.htm

Breakthrough finds molecules that block previously ‘undruggable’ protein tied to cancer

The findings, which could lead to a new class of cancer drugs, appear in the current issue of ACS Chemical Biology.

“These are the first reported small-molecule HuR inhibitors that competitively disrupt HuR-RNA binding and release the RNA, thus blocking HuR function as a tumor-promoting protein,” said Liang Xu, associate professor of molecular biosciences and corresponding author of the paper.

The results hold promise for treating a broad array of cancers in people. The researcher said HuR has been detected at high levels in almost every type of cancer tested, including cancers of the colon, prostate, breast, brain, ovaries, pancreas and lung.

“HuR inhibitors may be useful for many types of cancer,” Xu said. “Since HuR is involved in many stem cell pathways, we expect HuR inhibitors will be active in inhibiting ‘cancer stem cells,’ or the seeds of cancer, which have been a current focus in the cancer drug discovery field.”

HuR has been studied for many years, but until now no direct HuR inhibitors have been discovered, according to Xu.

“The initial compounds reported in this paper can be further optimized and developed as a whole new class of cancer therapy, especially for cancer stem cells,” he said. “The success of our study provides a first proof-of-principle that HuR is druggable, which opens a new door for cancer drug discovery. Many other RNA-binding proteins like HuR, which are so far undruggable, can also be tested for drug discovery using our strategy.”

The research team evaluated about 6,000 compounds from both the KU Chemical Methodologies and Library Development Center and the Food and Drug Administration in a process known as “High Throughput Screening,” hunting for compounds that obstruct HuR’s interface with healthy human RNA.

The KU researchers confirmed the potential of the most promising compounds with cutting-edge techniques like Amplified Luminescent Proximity Homogeneous Assay, surface plasmon resonance, ribonucleoprotein immunoprecipitation assay and luciferase reporter functional studies — verifying that six compounds with a similar “scaffold” could be starting points of novel cancer drugs to target the oncoprotein HuR.

“A cancer-causing gene, or oncogene, makes RNA, which then makes an oncoprotein that causes cancer or makes cancer cells hard to kill, or both,” Xu said. “This is the problem we’re trying to overcome with precision medicine.”

The scientist said the HuR-RNA binding site is like a long, narrow groove, not a well-defined pocket seen in other druggable proteins targeted by many current cancer therapies.

“HuR tightly binds to RNA like a hand,” Xu said. “The HuR protein grabs the ‘rope’ — or the RNA — at a site called ‘ARE’ on the rope. We aimed to find a small-molecule compound that makes the hand release the rope by competing with ARE of the RNA.”

The research took more than 3 1/2 years and involved the collaboration of chemists, cancer biologists, computer modeling experts, biochemists and biophysicists at KU — notably the labs of Xu, Jeffrey Aub� in the Department of Medicinal Chemistry and Jon Tunge in the Department of Chemistry.

Grants from the National Institutes of Health, along with funding from the state of Kansas, the Hall Family Foundation and Bold Aspiration funding from KU’s Office of the Provost, supported the work.

For Xu, the findings are reflective of a personal commitment to improving odds for people diagnosed with cancer, the second-largest killer in the U.S. after heart disease.

“Trained as medical doctor and Ph.D., with both a grandfather and an uncle who died of cancer, I devoted my career to cancer research and drug discovery — aiming to translate discovery in the lab into clinical therapy, to help cancer patients and their families,” he said. “We hope to find a better therapy — and eventually a cure — for cancer.”

source : http://www.sciencedaily.com/releases/2015/04/150409120453.htm

Stem cell disease model clarifies bone cancer trigger

The study results, published in the journal Cell, revolve around iPSCs, which since their 2006 discovery have enabled researchers to coax mature (fully differentiated) bodily cells (e.g. skin cells) to become like embryonic stem cells. Such cells are pluripotent, able to become many cell types as they multiply and differentiate to form tissues. The iPSCs can then be converted again as needed into differentiated cells such as heart muscle, nerve cells, bone, etc.

While some seek to use iPSCs as replacements for cells compromised by disease, the new Mount Sinai study sought to determine if they could serve as an accurate model of genetic disease “in a dish.” In this context, the dish stands for a self-renewing, unlimited supply of iPSCs or a cell line — which enables in-depth study of disease versions driven by each person’s genetic differences. When matched with patient records, iPSCs and iPSC-derived target cells may be able to predict a patient’s prognosis and whether or not a given drug will be effective for him or her.

In the current study, skin cells from patient with and without disease were turned into patient-specific iPSC lines, and then differentiated into bone-making cells where both rare and common bone cancers start. This new bone cancer model does a better job than previously used mouse or cellular models of “recapitulating” the features of bone cancer cells driven by key genetic changes.

“Our study is among the first to use induced pluripotent stem cells as the foundation of a model for cancer,” said lead author Dung-Fang Lee, PhD, a postdoctoral fellow in the Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai. “This model, when combined with a rare genetic disease, revealed for the first time how a protein known to prevent tumor growth in most cases, p53, may instead drive bone cancer when genetic changes cause too much of it to be made in the wrong place.”

Rare Disease Sheds Light on Common Disease

The Mount Sinai disease model research is based on the fact that human genes, the DNA chains that encode instructions for building the body’s structures and signals, randomly change all the time. As part of evolution, some code changes, or mutations, make no difference, some confer advantages, and others cause disease. Beyond inherited mutations that contribute to cancer risk, the wrong mix of random, accumulated DNA changes in bodily (somatic) cells as we age also contributes to cancer risk.

The current study focused on the genetic pathways that cause a rare genetic disease called Li-Fraumeni Syndrome or LFS, which comes with high risk for many cancers in affected families. A common LFS cancer type is osteosarcoma (bone cancer), with many diagnosed before the age of 30. Beyond LFS, osteosarcoma is the most common type of bone cancer in all children, and after leukemia, the second leading cause of cancer death for them.

Importantly, about 70 percent of LFS families have a mutation in their version of the gene TP53, which is the blueprint for protein p53, well known by the nickname “the tumor suppressor.” Common forms of osteosarcoma, driven by somatic versus inherited mutations, have also been closely linked by past studies to p53 when mutations interfere with its function.

Rare genetic diseases like LFS are good study models because they tend to proceed from a change in a single gene, as opposed to many, overlapping changes seen in more related common diseases, in this case more common, non-inherited bone cancers. The LFS-iPSC based modeling highlights the contribution of p53 alone to osteosarcoma.

Combining iPSC lines, and bone cancer driven by p53 mutations in LFS patients, the research team revealed for the first time that the LFS bone cancer results from an overactive p53 gene. Too much p53 in bone-making cells called osteoblasts dials down a gene, H19, and a related protein, decorin, that would otherwise help stem cells mature (differentiate) to become normal osteoblasts.

The inability of cells to differentiate makes them vulnerable to genetic mistakes that drive cancer, since more “stemness” means a tendency toward rapid, abnormal growth seen in tumors. One tragic feature of osteosarcoma is the rapid, error-prone production of weaker bone by cancerous bone-making cells, where a young person surprisingly breaks a bone to reveal undiagnosed, advanced cancer.

The research team found that the H19 gene may control a network of interconnected genes that fine-tunes the balance between cell growth and resistance to growth. Decorin is a protein that is part of connective tissue like bone, but that also plays a signaling role, interacting with growth factors to slow the rate that cells divide and multiply, unless turned off by too much p53.

“Our experiments showed that restoring H19 expression hindered by too much p53 restored “protective differentiation” of osteoblasts to counter events of tumor growth early on in bone cancer,” said co-author, Ihor Lemischka, PhD, Director of The Black Family Stem Cell Institute within the Icahn School of Medicine. “The work has implications for the future treatment or prevention of LFS-associated osteosarcoma, and possibly for all forms of bone cancer driven by p53 mutations, with H19 and p53 established now as potential targets for future drugs.”

source : http://www.sciencedaily.com/releases/2015/04/150409133210.htm

New approach to treat drug-resistant HER2–positive breast cancer

The discovery, published in the journal CELL Reports, provides the experimental evidence for the potential development of a novel combination therapy for HER2-positive breast cancer. The combination includes the FDA approved drug lapatinib and a new experimental drug called a BET bromodomain inhibitor, which works by disrupting the expression of specific genes.

This study, a collaboration of 20 University of North Carolina researchers, is the first time a BET bromodomain inhibitor has been shown to prevent the onset of resistance to drugs such as lapatinib in breast cancer cells.

“This research was done in cell lines of human HER2-positive breast cancer, not in patients; but the results are very striking,” said Gary Johnson, PhD, Kenan Distinguished Professor and chair of the department of pharmacology, member of the UNC Lineberger Comprehensive Cancer Center, and senior author of the paper. “The combination treatments are currently being tested in different mouse models of breast cancer. Our goal is to create a new kind of therapy that could help oncologists make the response to treatment more durable and lasting for breast cancer patients.”

The HER2-positive subtype accounts for 15 to 20 percent of all breast cancer diagnoses. Only about one-third of these patients respond well to standard therapy. But even patients that initially respond eventually develop resistance. This is a universal problem of drugs that target specific proteins called kinases that drive tumor growth. Kinases are essential for cellular activities, such as movement, division, and signaling to other proteins to promote cell survival and growth. In this subtype of breast cancer, HER2 is the primary kinase involved in the growth of these tumors. When it’s blocked with a drug like lapatinib, cancer cells have ways to get around the roadblock by using other kinases.

Tim Stuhlmiller, PhD, a postdoctoral fellow in Johnson’s lab and first author of the paper, conducted experiments using a technique to determine kinase activity on a global scale throughout a group of given cells – a technology that Johnson’s lab had previously developed.

Stuhlmiller was able to see what happened to HER2-positive human cancer cells when treated with the HER2 inhibitor lapatinib. As expected, each cell line developed resistance to the drug. But, surprisingly, each cell line resisted in different ways. Not just one or two kinases activated to beat the lapatinib. Many kinases responded. And they were not the same kinases from cell line to cell line. But they did the same thing: they ensured that the cancer cells survived and grew.

“It was amazing,” Stuhlmiller said. “We found this massive up-regulation of many different kinases that could either reactivate the main HER2 signaling pathway or bypass it entirely. In fact, we discovered that nearly 20 percent of the cell’s entire gene expression profile was dysregulated when we treated the cells with lapatinib.”

Dysregulated genes lead to abnormal amounts of proteins. These proteins – the kinases – drive resistance to anti-cancer drugs. This research strongly suggests that there are many different ways HER2-positive cancer cells can compensate for the initial blockage of the HER2 protein. Thus, targeting all of these specific kinases would be extremely difficult.

“Because of toxicity concerns, you couldn’t inhibit all these kinases that potentially help cancer cells compensate in the face of a HER2 inhibitor,” Stuhlmiller said. “The more drugs you try to use, the more toxic that would be for patients and the lower the dose people would be able to tolerate.

“So that’s one take home message,” he said. “But the main message is we used a different kind of drug to block that entire massive kinase response before it ever happened.”

For that, Johnson’s team used a BET bromodomain inhibitor. It’s part of a new class of drugs that targets proteins involved in gene transcription – when particular parts of DNA are copied into RNA; this is the first step in the creation of enzymes, such as kinases.

Johnson’s team tested several BET bromodomain inhibitors, including one currently in clinical trials to treat blood cancers and a specific type of leukemia. During experiments, Johnson’s team found that BET bromodomain inhibitors targeted the gene transcription of most of the kinases responsible for resistance. By combining lapatinib with a BET bromodomain inhibitor, Stuhlmiller found that the HER2 kinase was blocked, as planned. Also, the massive kinase activation that typically followed HER2 inhibition never happened. The second drug suppressed the kinase response.

“We blocked it before it could happen,” Stuhlmiller said. “In all five cell lines we tested, there were no cancer cells left because the combination therapy blocked their growth. Essentially, we made the activity of lapatinib durable.” As a result, the cancer cells were annihilated.

Johnson’s lab and their UNC collaborators are currently working to replicate their findings in animal models of HER2-positive breast cancer. They think these types of combination therapies are going to be necessary to prevent resistance in the clinic. They’re also studying the effects of BET bromodomain inhibitors on other breast cancer subtypes, such as triple-negative breast cancer, another subtype that is difficult to treat.

source : http://www.sciencedaily.com/releases/2015/04/150409133220.htm

Study revises theory of how PTEN, a critical tumor suppressor, shuts off growth signals

Today, scientists at Cold Spring Harbor Laboratory (CSHL) publish new evidence explaining precisely how the protein encoded by PTEN (called PTEN) works — specifically, how it is recruited to particular locations in our cells where pro-growth signals need to be shut off.

The new evidence, assembled by a team led by CSHL Associate Professor Lloyd Trotman, contradicts a long-held assumption about PTEN function, and could help scientists design more effective drugs to counteract cancer’s hallmark trait, uncontrolled cellular growth.

“A whole generation of cancer investigators, including me, has been taught that PTEN performs its crucial role at the plasma membrane, which is what separates the inside of cells from the outside environment” Trotman explains. The exterior surface of the membrane is dotted with receptor molecules — switches which growth factors can flip on from the outside to transmit growth cues into the cell’s interior.

Normally, these switches are off, and no signals are transmitted. Every once in a while, however, a pro-growth-hormone molecule docks at a receptor on the surface, setting off a cascade of biochemical events inside the cell. “With respect to growth, the brakes are normally on,” says Trotman. In the cell membrane, fatty molecules are decorated with the equivalent of traffic signals, and “in the default mode, the light is red.” But when a growth factor switches on a receptor, special enzymes change the light embedded in the membrane from red to green. Then, after the signal is transmitted further into the cell’s interior, it is time to switch the signal back to red. This is the job of the PTEN protein.

Since the discovery of these fundamental signaling mechanisms about 15 years ago, scientists have assumed that PTEN performs this crucial task at or near the interior surface of the cell membrane. But how does it get there? And where does it comes from? When Trotman and colleagues imaged the interior of ordinary cells, they found PTEN proteins everywhere — not just near the membrane, but virtually everywhere throughout the three-dimensional space of the cells [see image 1]. Prevailing theory did not consider this a problem: “it had PTEN bouncing around, all over the cell, and abundant enough so that it was always available near the membrane,” to switch a green growth signal back to red.

“What we found was that PTEN is not, as the theory suggests, literally bouncing off the walls of the cell in random fashion,” Trotman says. “Using super-resolution microscopy, the technology that was awarded last year’s Nobel Prize in chemistry, we were able to discover an organizing principle at work.” The team was amazed to find a consistent association, throughout cells: the location of PTEN proteins closely coincided with the presence of tiny highways called microtubules that crisscross throughout every cell.

PTEN proteins travel along microtubule highways to where they are needed. But how do they know when and where, precisely? In a paper appearing in Molecular Cell, Trotman’s team explains that green signals ready to be turned to red are literally pinched off from the cell membrane in tiny bubble-like structures called vesicles. This process is called endocytosis. The vesicles are coated with a protein called clathrin, which helps the vesicles to take spherical shape. Later, the coating is dissolved, exposing the naked green signal as well as a magnet-like signal to attract PTEN. This is the moment, according to Trotman’s team, when PTEN is recruited. PTEN then binds the vesicle bearing the green signal and performs its essential service: it removes a phosphate group from the signal (a process called de-phosphorylation), turning the signal back to red.

Trotman’s group demonstrates how PTEN’s structure is precisely evolved to do the job. One domain of the protein is structured to bind to the magnet; its other domain catalyzes the phosphate-removing reaction. “It is quite an elegant mechanism,” Trotman says. “It is highly efficient. And in view of PTEN’s critical role as a tumor suppressor, it’s also important that the process we uncovered is a controlled one, not random as was previously believed.”

Many observed facts “fall into place” with the new explanation of how PTEN works. “Now we understand this fundamental process. We understand that taking growth signals inside the cell via vesicles, is directly related to the process of turning them off. The vesicle is essentially packaging. Once the growth signal gets packaged, it’s being readied to be shut off.”

source : http://www.sciencedaily.com/releases/2015/04/150409133513.htm

Review highlights potential of cancer immunotherapy plus targeted therapy

“To support this goal and accelerate these efforts, changes in directions of research support and funding may be required,” co-authors Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology, and Jim Allison, Ph.D., chair of Immunology, said in the review.

The review, titled “Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential,” covers the strengths and weaknesses of the two forms of therapy and notes how their combination could be particularly potent.

While individual researchers and pharmaceutical companies are studying and developing both types of drugs, a major initiative is needed to understand how both drug types might best work together, Sharma and Allison note.

“Without a major initiative, it will be harder to make progress because the groups focused on genomically targeted therapy and the checkpoint blockade researchers will largely stay in their own camps,” Sharma said.

Targeted therapy: Frequent but short-lived responses

The molecular mechanisms involved in the development of cancer have been uncovered by extensive research over the past 30 years, culminating in The Cancer Genome Atlas, a National Institutes of Health project that identified and characterized many genetic mutations that fuel cancer.

Drugs that hit a specific genomic defect that drives a patient’s cancer provoke good initial responses in most patients, the review notes. For example, drugs that target a specific BRAF gene mutation commonly found in melanoma shrink tumors in about half of patients with the mutation.

However, resistance almost always develops because tumors harbor multiple genomic defects capable of driving the disease after a targeted drug knocks down one driver. BRAF inhibitors prolonged median survival in clinical trials by about seven months.

Checkpoint blockade: Fewer but stronger results

Allison pioneered immune checkpoint blockade, an approach that treats the immune system, rather than the tumor directly, by blocking molecules on T cells that shut those attack cells down, protecting tumors from immune response.

The first such drug, called ipilimumab (Yervoy), developed out of Allison’s basic science research, showed much lower response rates against advanced melanoma than those obtained with targeted drugs, but long-term follow-up found that 22 percent of those treated with Yervoy survived at least four years, unprecedented results for the disease. Importantly, those who survived three years have gone on to live up to 10 years and beyond.

Drugs that hit other immune checkpoints have been developed after Yervoy and show similar response rates in a variety of cancers.

Immunity is key to long-term responses

Knowing that the immune system is capable of recognizing distinctive features of cancer cells and launching a T cell attack against those tumor antigens, and that checkpoint blockade removes a roadblock to that attack, it’s logical that these drugs should work against many tumor types. But the impact varies across cancers.

“We need to understand why some patients don’t respond to immunotherapy,” Allison said. But in others, the response is dramatic, as evidenced by the long-term survival of the those melanoma patients.

The immune system is custom made to deal with the problem of genomic diversity of tumors, Allison said.

“T cells are specific; they recognize and attack tumor-specific antigens down to the peptide level. They remember those target antigens forever, so they can thwart recurrence,” Allison said. “And finally, T cell response is adaptable, generating custom T cells to match multiple targets found in the genomic diversity of the tumor or generated by new mutations.”

How combinations might work

There’s a school of thought, Sharma notes, that combining multiple genomically targeted therapies might prove effective. However, evidence suggests that tumor genomic diversity might still defeat such combinations, and that it’s axiomatic in oncology that side effects increase in number and intensity as more drugs are added to treatment.

Targeted therapies might act as effective cancer vaccines, killing tumor cells and releasing new target antigens for T cells to identify and associate with tumors. And they might vary in their ability to enhance or inhibit immune response, because little is known right now about how targeted agents affect the immune system, Sharma said.

Early efforts to combine approaches have yielded interesting results. One phase I trial of an immune checkpoint blockade drug combined with two established targeted therapies yielded 40-50 percent response rates among patients with metastatic kidney cancer. Follow-up has not been long enough to determine durability of responses or impact on survival.

Two clinical trials combining Yervoy with two different BRAF inhibitors in melanoma illustrate potential issues for combination therapy. In one case, liver toxicity led to closure of the trial, while the other combination appears well-tolerated as the trial continues.

“This highlights that differences in drugs, doses and dosing schedule need to be evaluated as we develop combination therapies,” Sharma said.

While checkpoint blockade drugs currently focus on blocking two checkpoint mechanisms, others have been identified by research, as well as molecules that stimulate immune response. These provide new targets for immunotherapy. Facing multitudes of possible drug combinations, more effective preclinical research could make the choosing of such combinations for clinical trials more precise.

The two investigators address such issues in their leadership roles of the immunotherapy platform for MD Anderson’s Moon Shots Program. The program is designed to accelerate the conversion of scientific discoveries into clinical advances that significantly reduce cancer deaths.

Enhanced support for immunotherapy

Sharma and Allison close by noting that federal funding for cancer research has been “overwhelmingly directed toward genomically targeted therapies.” While Allison’s early research that led to Yervoy was funded by the National Cancer Institute, “since then, there have been no major initiatives to accelerate progress in this area.”

They suggest allocating greater resources to research focused on immune checkpoint therapies and targeted/immunotherapy combination therapies with “curative potential.”

They conclude: “At this stage, it does not seem a stretch to say that increasing funding to combination therapies will be key to development of new, safe treatments that may prove to be curative for many patients with many types of cancer.”

source : http://www.sciencedaily.com/releases/2015/04/150409133519.htm

Golgi trafficking controlled by G-proteins

The study is reported online April 9 in Developmental Cell.

“Our work provides the first direct evidence that G proteins are signaling on membranes inside cells, not just at the cell surface as has been widely believed for several decades,” said Pradipta Ghosh, MD, associate professor and senior author. “This is significant because the G-protein pathway is a target of at least 30 percent of all current drugs on the market.”

Specifically, the UC San Diego-led team used live cell imaging of fluorescent proteins and other biological assays to show that G proteins in cultured human cells are active on a series of pancake-shaped membranes, called the Golgi body. The Golgi body sorts, packages and directs the distribution of newly synthesized proteins to various locations within a cell. It also secretes enzymes, including matrix metalloproteases that enable cancer cells to digest surrounding tissue, escape and spread.

In addition to documenting G protein activity on the Golgi, scientists also identified the protein that turns on G proteins as GIV, widely recognized in the cancer research community for its role in facilitating metastasis. When GIV was inhibited, G proteins were shown to remain inactive on the Golgi and secretion of enzymes and other proteins was delayed.

“We’ve identified a new mechanism that may contribute to the progression of chronic diseases like cancer,” Ghosh said. “Prior to the study, the role of GIV in mediating cancer metastasis was ascribed to its ability to activate G proteins near the cell surface. We now know that targeting GIV and G proteins is a double whammy that inhibits key cancer-driving signals near the cell surface as well as secretion from the Golgi that may contribute to metastasis.”

source : http://www.sciencedaily.com/releases/2015/04/150409150810.htm

Advocate uses genetic history to increase knowledge of hereditary cancer risk

The 33-year-old mother who has tested positive for the BRCA2 cancer gene is one of 12 people in her family over three generations linked to the gene or diagnosed with cancer.

Now Koszegi is using her family’s genetic history to contribute to cancer research, prevention and treatment — with the aim of improving the quality of life for those facing hereditary risk.

“Cancer has always been part of my life,” said Koszegi, owner of Brushed Inc., a professional makeup, hair and wardrobe styling business. “Even though it has always been there, I want to aggressively monitor and protect my health and be my own advocate, and I want the same for my family members.”

Koszegi’s efforts began with enrolling herself and her cousins in the Gilda Radner Hereditary Cancer Program, part of the Women’s Cancer Program at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute.

Founded in 1991, the program consists of several research studies for women at higher risk for breast and ovarian cancer.

Led by Beth Y. Karlan, MD, the program works to gain a better understanding of the relationship of genes to the growth of specific cancers, and to understand why some mutation carriers develop breast, ovarian and other types of cancer, while other mutation carriers do not.

“Family is an essential part of our program,” said Karlan, director of the Women’s Cancer Program.

Koszegi traces her family’s history of cancer to her maternal grandfather and his siblings. In all, five of the seven siblings were diagnosed with breast or prostate cancer.

Prostate cancer claimed the life of Koszegi’s grandfather. Two of his daughters — including Koszegi’s mother and aunt — were diagnosed with breast cancer. Her mother died from the disease at 58 and her aunt is in remission.

Of the family’s current generation, six women, including Koszegi, have tested positive for the BRCA2 gene mutation, putting them at a higher risk for developing breast and ovarian cancer. No male cousins have been tested, though they each have young daughters. Koszegi’s 5-year-old son also is too young to be tested.

Koszegi looks forward to recruiting additional family members to the Gilda Radner Hereditary Cancer Program.

“I want to know why the BRCA mutation is so strong in my family,” she said.

More Information About Rachel Koszegi

With her family’s support, Rachel Koszegi underwent a prophylactic mastectomy in July 2014 to cut her risk of being diagnosed with breast cancer and in the future, plans to undergo a prophylactic oophorectomy to decrease her risks of ovarian cancer.

“The decision and process of undergoing prophylactic surgery was tough, but worth it,” said Koszegi.

And somehow in the midst of her busy schedule, Koszegi has found time to raise even more awareness — this time, outside of only her family. She’s embarking in a new organization that she and three female cousins created to shift the focus from the ugliness of cancer to the lives of women with the disease and their personal stories.

source : http://www.sciencedaily.com/releases/2015/04/150410095529.htm

Dual therapy’s 1-2 punch knocks out drug-resistant lung cancer

In experiments that combined the drug the patient had taken with a second compound that blocks off this newly discovered resistance pathway, the researchers were able to durably wipe out cancer cells in mice implanted with cells from the drug-resistant tumor.

“Even in cancers that are responding to targeted therapy by conventional criteria, resistance is already developing,” said the senior author of the new study, Trever Bivona, MD, PhD, assistant professor of medicine and member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). “In this work we have begun to crack open the question of why residual disease persists after targeted therapy.”

Between 10 and 35 percent of non-small cell lung cancer (NSCLC) patients carry mutations in a gene that codes for a cell-surface protein called the epidermal growth factor receptor, or EGFR. As its name suggests, under normal circumstances, when a growth factor protein locks onto the EGFR, the receptor sends signals that prompt cells to divide and proliferate. But the EGFR mutations seen in NSCLC cause the receptor to be stuck in an “on” position, leading to rampant cell proliferation.

Over the past decade, medications such as erlotinib (trade name Tarceva), which precisely targets the EGFR and tamps down its activity, have advanced the treatment of EFGR-mutant NSCLC beyond chemotherapy, but significant challenges remain. As many as 30 percent of patients exhibit so-called primary resistance to EGFR inhibitors, in which the drugs have no detectable effect. And among patients who do respond, almost all have an incomplete response leading to acquired resistance, in which drug-resistant cells that survive treatment form residual, often lethal, tumors.

Understanding the biological basis of acquired resistance has proved difficult, partly because patients with late-stage lung cancer rarely undergo surgery, leaving scientists with few drug-resistant tumors to use in research. But as described in the online edition of Cell Reports on April 2, 2015, a team of UCSF researchers recently had unusual access to a surgically resected tumor from an EGFR-mutant lung cancer patient who had experienced a substantial, but incomplete, response to erlotinib.

Led by first authors Collin Blakely, MD, PhD, a clinical instructor at UCSF, and Evangelos Pazarentzos, PhD, a postdoctoral fellow, the research group analyzed cells from this tumor using next-generation genome sequencing in an effort to understand how the cells sidestepped erlotinib treatment. They found that the tumor cells retained the EGFR mutation targeted by erlotinib and had not acquired additional cancer-driving mutations, or any other mutations known to confer drug resistance. These results suggested that the cells were still potentially susceptible to erlotinib, but had enlisted some additional mechanism to survive treatment.

That mechanism was revealed when cells from the tumor were implanted in mice that were then treated with erlotinib. The drug effectively inhibited EGFR activity, but the researchers also observed a rapid, 10-fold increase in the activity of a pathway known as NF-kappa-B, and they discovered that this increase is mediated by a previously unknown biochemical complex formed within the tumor cells. Though primarily associated with the immune system, a growing body of work has tied the NF-kappa-B pathway to various forms of cancer.

An experimental drug known as PBS-1086 directly targets the NF-kappa-B pathway, and when the researchers coupled this drug with erlotinib, the implanted tumors shrank significantly, suggesting that combining a compound like PBS-1086 with erlotinib at the outset of therapy may help to prevent acquired drug resistance in EGFR-mutant NSCLC.

Combined drug regimens designed to overcome drug resistance at the outset of therapy are now the norm in treating certain forms of melanoma, said Bivona, and he believes PBS-1086 “has a shot” to play a similar role in NSCLC.

“The NF-kappa-B pathway is engaged by cells in response to EGFR inhibitors as a way to survive treatment,” Bivona said. “Excitingly, if we block that pathway with a novel drug while simultaneously administering the EGFR inhibitor, we see tumors shrink. In lung cancer patients treated with these drugs, and that’s a substantial number of patients, this could be a very powerful companion therapy to minimize or eliminate residual disease.”

source : http://www.sciencedaily.com/releases/2015/04/150402132753.htm