The results suggest that bexarotene could possibly help the approximately 5.4 million Americans with Alzheimer’s disease, according to the neuroscientists at Case Western Reserve University School of Medicine.

However, while studies involving animals can be useful, they often fail to produce similar results in humans.

Bexarotene is approved in the United States to treat skin problems caused by cutaneous T-cell lymphoma.

The body’s inability to clear amyloid beta from the brain is a major factor in the development of Alzheimer’s disease, according to a university news release. Previous research showed that the main cholesterol carrier in the brain, apolipoprotein E (ApeE), plays an important role in clearing amyloid beta proteins.

In this study, the researchers found that bexarotene increased ApoE expression, and the elevated levels of ApoE boosted clearance of amyloid beta from the brain. Bexarotene stimulates retinoid X receptors (RXR), which are proteins that control the production of ApoE.

Within six hours of receiving bexarotene, soluble amyloid levels in the mice fell by 25 percent and the effect lasted for three days. This decrease was associated with rapid improvement in a wide number of behaviors in mice with Alzheimer’s, according to the release.

In addition, bexarotene treatment also rapidly stimulated the removal of amyloid plaques from the brain, the researchers said. The plaques are accumulations of amyloid that form in the brain and are a hallmark of Alzheimer’s disease.

“This is a particularly exciting and rewarding study because of the new science we have discovered and the potential promise of a therapy for Alzheimer’s disease,” study senior author Gary Landreth, a professor of neurosciences, said in a university news release.

“We need to be clear; the drug works quite well in mouse models of the disease. Our next objective is to ascertain if it acts similarly in humans. We are at an early stage in translating this basic science discovery into a treatment,” he added.

The study appeared Feb. 9 in the journal Science.

SOURCE: Case Western Reserve University, news release, Feb. 7, 2012

The researchers identified two mutations in an important gene known as the histone H3.3. This gene is key in modulating genetic expression. “These mutations prevent the cells from differentiating normally and help protect the genetic information of the tumor, making it less sensitive to radiotherapy and chemotherapy,” says Dr. Nada Jabado, hematologist-oncologist at The Montreal Children’s Hospital of the McGill University Health Centre and principal investigator of the study.

“This research helps explain the ineffectiveness of conventional treatments against cancer in children and adolescents — we’ve been failing to hit the right spot,” says Dr. Jabado. “It is clear now that glioblastoma in children is due to different molecular mechanisms than those in adults, and should not be treated in the same way. Importantly, we now know where to start focusing our efforts and treatments instead of working in the dark.”

Inappropriate regulation of this gene has been observed in other cancers such as colon, pancreatic, lymphoma, leukemia and pancreatic neuroendocrine cancer, and future research could therefore reveal improved treatments for these diseases.

Brain tumours are the primary cause of death for children with cancer in Europe and North America. The diagnosis of glioblastoma in a child or adolescent remains a death sentence and about 200 children in Canada die every year of this cancer. Most children will die within the two years of their diagnosis regardless of treatment.

Erivedge, reviewed under the agency’s priority review program, is the first FDA-approved drug for metastatic basal cell carcinoma. Erivedge was reviewed under the FDA’s priority review program that provides for an expedited six-month review of drugs that may offer major advances in treatment.

Basal cell carcinoma is generally a slow growing and painless form of skin cancer that starts in the top layer of the skin (epidermis). The cancer develops on areas of skin that are regularly exposed to sunlight or other ultraviolet radiation.

Erivedge is a pill taken once a day and works by inhibiting the Hedgehog pathway, a pathway that is active in most basal cell cancers and only a few normal tissues, such as hair follicles.

“Our understanding of molecular pathways involved in cancer, such as the Hedgehog pathway, has enabled the development of targeted drugs for specific diseases,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approach is becoming more common and will potentially allow cancer drugs to be developed more quickly. This is important for patients who will have access to more effective therapies with potentially fewer side effects.”

The safety and effectiveness of Erivedge was evaluated in a single, multi-center clinical study in 96 patients with locally advanced or metastatic basal cell carcinoma. The clinical study’s primary endpoint was objective response rate (ORR) or the percentage of patients who experienced complete and partial shrinkage or disappearance of the cancerous lesions after treatment. Of the patients with metastatic disease receiving Erivedge, 30 percent experienced a partial response and 43 percent of patients with locally advanced disease experienced a complete or partial response.

The most common side effects observed in patients treated with Erivedge were muscle spasms, hair loss, weight loss, nausea, diarrhea, fatigue, distorted sense of taste, decreased appetite, constipation, vomiting, and loss of taste function in the tongue.

Erivedge is being approved with a BOXED WARNING alerting patients and health care professionals of the potential risk of death or severe birth effects to a fetus (unborn baby). Pregnancy status must be verified prior to the start of Erivedge treatment. Male and female patients should be warned about these risks and the need for birth control. Erivedge is marketed by South San Francisco based-Genentech, a member of the Roche Group.

“When we first started working on kidney cancer in the early 1980s, it was thought of as a single disease, and all kidney cancers were treated the same,” said Dr. W. Marston Linehan, chief of the NCI’s Urologic Oncology Branch.

Then, as now, surgery was the first treatment for renal cell carcinoma (RCC), the most common type of kidney cancer, which had not spread. Once the cancer had metastasized, however, patients generally had a poor prognosis and most did not survive more than a year.

“Kidney cancer was thought to be this disease that inexorably led to death,” said Dr. George Philips, a researcher at Georgetown Lombardi Comprehensive Cancer Center.

Because traditional chemotherapy is not effective in kidney cancer, Dr. Philips continued, patients with advanced disease were treated with cytokines, either interleukin-2 or interferon alpha, both of which have considerable toxic side effects. Only 5 to 10 percent of patients treated with high-dose interleukin-2 experienced a complete and lasting response.

To try to improve conditions for these patients, Dr. Linehan and his colleagues from across the National Institutes of Health (NIH) began recruiting families that had multiple members with kidney cancer. “We wanted to identify what we thought was the gene for kidney cancer,” said Dr. Linehan. “Our hope was, if we could understand the gene that causes kidney cancer, that [understanding] could possibly provide the foundation for developing a targeted therapeutic approach.”

Ten years later, the researchers identified mutations in a gene called VHL in patients with von Hippel-Lindau syndrome, a hereditary cancer syndrome in which patients develop kidney tumors with a specific histology, or cellular organization, known as clear cell RCC. They subsequently determined that the VHL gene was also mutated or silenced in most non-hereditary clear cell RCCs, suggesting that VHL was the kidney cancer gene they were seeking.

This discovery led researchers to test therapies that target the VHL pathway, and today there are six drugs approved by the Food and Drug Administration to treat patients with advanced clear cell RCC: vascular endothelial growth factor (VEGF) receptor inhibitors (sorafenib, sunitinib, and pazopanib); a VEGF-binding antibody (bevacizumab); and inhibitors of the mTOR pathway (temsirolimus and everolimus), another VEGF regulator. Although many patients benefit significantly from these agents, few patients are cured.

Multiple Genes, Multiple Diseases

Nearly three-quarters of RCC tumors have clear cell histology. The rest, however, display a variety of other histologic patterns. To evaluate the genetic basis of these rarer cancers, Dr. Linehan and his colleagues studied families with non-clear cell RCC. From some of these families they identified a new form of kidney cancer, called hereditary papillary renal carcinoma (HPRC).

Families with HPRC did not have the clinical characteristics of von Hippel-Lindau syndrome, nor did they have VHL gene mutations. Instead, the researchers identified mutations in the proto-oncogene MET, and showed for the first time that a different gene could cause a different type of kidney cancer.

The team wondered if this was a fluke, or if other RCC histologic types were associated with mutations in additional genes. When they examined families with Birt-Hogg-Dubé, a syndrome characterized by multiple skin lesions, the researchers determined that these patients developed chromophobe and oncocytic RCCs. Unlike the clear cell and papillary tumors, these tumors had alterations in a new gene that the group named FLCN.

In addition, another research group found that patients with hereditary leiomyomatosis RCC, a very aggressive form of kidney cancer that Dr. Linehan’s group had been studying since the late 1980s, have mutations in fumarate hydratase, an enzyme that plays an essential role in the metabolic process that cells use to generate energy from glucose. To date, investigators have identified 15 different genes that cause distinct types of kidney cancer.

“Today we know that kidney cancer is not a single disease,” commented Dr. Linehan. “It’s made up of a number of different types of cancer, each with a different histologic type, with a different clinical course, responding differently to therapy, and caused by [mutations in] different genes. But each of these genes is fundamentally involved in the same pathway: the cell’s ability to sense oxygen, iron, nutrients, or energy. We have concluded that kidney cancer is fundamentally a metabolic disease.”

The Search for More Effective Treatments

Since as many as 20 percent of newly diagnosed patients will have metastatic disease, researchers are far from where they want to be, even with the well-studied clear cell type of RCC, commented Dr. Michael Atkins, leader of the Kidney Cancer Program at the Dana-Farber/Harvard Cancer Center. “We want to produce durable responses in the majority of patients,” he said.

To improve patient outcomes, current studies are examining which treatment a patient should receive first based on the characteristics of his or her tumor, the optimal doses and schedules for current treatments, and the best sequence to use for available therapies. Because these tumors are highly vascular, imaging techniques, such as functional magnetic resonance imaging (fMRI) or positron emission tomography (PET), may allow researchers to observe subtle treatment effects and modify treatment accordingly.

Other groups, Dr. Atkins continued, are developing more selective inhibitors of the VEGF receptor. These more selective agents may allow clinicians to combine therapies to produce synergistic tumor-fighting activity while sparing patients the side effects associated with less-selective agents. The limited success of cytokine therapy, which activates the immune system, has prompted researchers to investigate the use of novel, more potent immunotherapies.

Researchers are also trying to tease out the pathways tumors use to resist current therapies in order to develop new drugs that target these pathways. Likewise, discovery of the genes that regulate the non-clear cell RCC subtypes has provided numerous potential drug targets. For example, Dr. Linehan’s group is conducting trials of agents targeting fumarate hydratase.

Investigators may need to change the design of clinical trials to study the less-common non-clear cell cancers and to evaluate overall survival differences for all RCC therapies more stringently. Additionally, programs such as The Cancer Genome Atlas continue to look for new genes and pathways that regulate RCC, with the aim of developing novel therapy targets.

“I think there has been enormous progress made in kidney cancer,” said Dr. Linehan. “Do we need to do better? Of course! But I am very encouraged about the future.”

Now, a new study by researchers at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, and colleagues identifies the specific genetic mechanism that causes this side effect.

“What we found is that vemurafenib blocks the mutation that makes the melanoma grow, but when patients have skin cells with another mutation that’s probably induced from sun exposure, there the drug has the exact opposite effect and causes these squamous cell cancers to grow,” said Dr. Antoni Ribas, co-senior author of the study and an associate professor of hematology/oncology at UCLA.

What’s more, the findings suggest that combining vemurafenib, a BRAF inhibitor, with a drug called an MEK inhibitor — which blocks the other mutation — may not only prevent this side effect, but may also lead to an even more effective melanoma treatment, Ribas said.

“It needs to be demonstrated in clinical trials, but the theory is that if we give these two medications together up front, we will be punching the melanoma where it really hurts twice, and also preventing the growth of secondary skin cancers,” Ribas said.

In experiments in mice with the RAS mutation, the researchers showed that the combination of a BRAF inhibitor and an MEK inhibitor successfully blocked the growth of squamous cell cancers.   This result may need replication in humans, since many findings in animals do not translate into effective treatments for people.

Ribas noted that the findings have implications beyond just melanoma, since RAS mutations are common in lung, pancreatic and colon cancer. “What this data also warns us is that we have to be very careful about using BRAF inhibitors in a setting where we don’t know what other mutations may be driving [the cancer],” he said. >> Read Full Story at Medline Plus

“I wasn’t surprised at all,” said Dr. Otis Brawley, chief medical officer of the American Cancer Society, who wasn’t involved in the study. “Unfortunately, robotic prostatectomy — like many things in prostate cancer — has gotten a lot more hype than it should.”

Robotic prostatectomy has caught on rapidly in the U.S., despite the fact that there’s no good evidence to show it’s better than traditional prostate removal. It is, however, much more costly, adding some $2,000 in hospital costs per procedure.

The new study, published in the Journal of Clinical Oncology, is based on responses from more than 600 prostate cancer patients on Medicare, the government’s health insurance for the elderly. About 400 of them had so-called robotic-assisted laparoscopic prostatectomy, in which the surgeon uses a robot to access the prostate through multiple small holes in the belly. The rest of the patients had traditional open surgery, in which the prostate is removed through one long cut in the belly.

Nearly nine out of 10 men had a moderate to major problem with sexual functioning 14 months after their surgery, Dr. Michael Barry of Massachusetts General Hospital in Boston and colleagues found. And about a third of the men said they had incontinence after their surgery.

Overall, there were no differences between the two patient groups, although urinary problems appeared to be slightly more common after the robot procedure.

An editorial in the journal called the findings “sobering,” but added that it’s hard to compare the two procedures directly based on the new data. It’s possible, for instance, that men with high hopes for the robot procedure would be more bothered by side effects afterward.

“The problem that is revealed in this paper is this question of expectations,” said Dr. Matthew Cooperberg, a urologist who co-wrote the editorial. Heavy promotion has catapulted robot surgery to its current status. Out of the tens of thousands prostate removals done annually in the US, some 85 percent are estimated to be robotic.

“To some extent it’s the manufacturer, to an extent it’s surgeons, to an extent it’s a culture that tends to put great faith in technology, even when the patient doesn’t understand it,” said Cooperberg, of the University of California, San Francisco.

“The robot is impressive technology, allowing the surgeon to sit at a console and direct a camera and two or three laparoscopic arms with six degrees of wristed motion for cutting, retracting, cauterizing, or suturing — all with high magnification and three-dimensional visualization,” Cooperberg and his colleagues write.

The robots, which cost a couple of million dollars each, do have some advantages. For instance, they reduce blood loss, which helps surgeons see better when operating.

But Cooperberg, who uses the technology himself, readily acknowledges that it probably doesn’t treat cancer any better than the old surgery and doesn’t have proven benefit in terms of side effects.

He said patients considering surgery should look for experienced surgeons rather than focus on technology.

‘WEIGH YOUR OPTIONS’

Many men with early-stage prostate cancer might not need treatment at all. One study found that more than 120,000 American men diagnosed with prostate cancer every year are ideal candidates for observation, or watchful waiting. Still, the majority of them end up having surgery, radiation, or other treatment instead.

“For a man who wants to be aggressively treated I use that study to say: sit down and rationally choose what procedure to use. You have time,” Brawley told Reuters Health.   >> Read Full Article

“We are making progress from the neck down in cancer treatment, but brain metastases are increasing and are often a primary reason patients with breast cancer do not survive,” said Patricia S. Steeg, Ph.D., head of the Women’s Cancers Section at the National Cancer Institute’s Center for Cancer Research.

Steeg, who is also a deputy editor of Clinical Cancer Research, another journal of the AACR, said very few drugs that are effective for the treatment of breast cancer break what scientists call the “blood–brain barrier” and treat disease established inside the brain.

Scientists are striving to understand the mechanisms and effects of brain cancer metastasis.

Steeg and colleagues observed the role of pigment epithelium-derived factor (PEDF) on metastatic breast cancer cell lines. PEDF is currently being studied as a therapy for macular degeneration because it has been shown to protect neurons in the retina.

Researchers found that PEDF managed to suppress the brain metastatic activity of these lines. Furthermore, it exerted a prosurvival effect on neurons and shielded the brain from tumor-induced damage. Specifically, there was a 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF.

Although further research is needed to confirm these findings and their applicability, Steeg said the findings represent a significant step forward in trying to manage this condition. >> Link to Release

The pill is aspirin, and a host of studies have suggested that it can prevent and possibly reduce the risk of dying from some cancers. The data in support of aspirin’s anticancer effects recently received another boost, with one of the largest analyses to date—a meta-analysis of eight clinical trials involving regular aspirin use, published online December 6, 2010 in The Lancet—showing a substantial reduction in mortality for a number of different cancers.

As is often the case, though, the story is not that simple. None of the trials included in the meta-analysis, for example, was designed specifically to assess whether aspirin reduces cancer incidence or mortality. And although many studies, including a few clinical trials, support the notion that aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of developing or dying from some cancers, other studies, including clinical trials, have reached a different conclusion.

Lots of Data, but Still Unknowns

The meta-analysis, led by Dr. Peter Rothwell from the University of Oxford, found that after 5 years of follow-up, trial participants who took aspirin daily—regardless of dose—for a mean of 4 years had a 44 percent reduced risk of dying from cancer compared with participants who took a placebo. The largest decrease in risk was for gastrointestinal cancers.

One of the strong points of the meta-analysis, noted Dr. Rothwell, is that it included 20 years of follow-up data for individual participants in three of the eight trials, rather than relying solely on combined data from the original studies. In this subset of patients, there was a 20 percent lower risk of dying from cancer after 20 years, with the largest benefit seen again for gastrointestinal cancers. Overall in the meta-analysis, trial participants who took aspirin had a decreased risk of dying from relatively rarer but highly deadly cancers such as pancreatic and esophageal, as well as from common cancers such as lung and prostate. The longer the duration of aspirin use in the trials, the greater the benefit.

Recently, a similar meta-analysis from the same research team, this one focused specifically on the effect of aspirin use on colorectal cancer, showed large and statistically significant reductions in both incidence and death from the disease. The finding, the study team pointed out, is consistent with results from numerous studies that have shown regular NSAID use reduces or prevents the growth of precancerous growths in the colon.

But, “It would be premature to recommend that people start taking aspirin specifically to prevent cancer,” said Dr. Eric Jacobs, strategic director of pharmacoepidemiology for the American Cancer Society. Potential side effects have to be taken into consideration, he continued, noting that even low dosages of aspirin “can substantially increase the risk of serious gastrointestinal bleeding.”

Dr. Rothwell predicts that the findings from these and other studies will “firm up the evidence” in support of aspirin for cancer prevention.  In the meantime, Dr. Jacobs advised, the average person needs to proceed with an abundance of caution. “Decisions about aspirin use should be made by balancing the risks against the benefits,” he said, “so any decision about daily aspirin use should be made only in consultation with your health care professional.”  >> Read Full Article

The concept of tumor self-metastasis, or tumor “self-seeding,” originated at Memorial Sloan-Kettering Cancer Center, based on a series of studies led by Drs. Joan Massagué, head of the Metastasis Research Center, and Larry Norton, deputy physician-in-chief of the center’s breast cancer programs.

In studies of mice, Dr. Massagué observed that breast tumors expressing genes associated with metastasis were growing faster than tumors that didn’t express these genes, even though the genes had no apparent role in increased cell division or decreased cell death. “Moreover, the fraction of dividing cells was not higher in fast-growing tumors versus tumors that are slower growing,” explained Dr. Norton.

These results did not fit in with the standard theories of tumor growth. In 2006, the two researchers proposed that cells that break free from a tumor and colonize distant tissues may also return home via the circulatory system to the welcoming microenvironment in which they first developed.

“We started discussing the possibility that maybe some tumors are growing faster not because the cells were dividing faster or because there was a higher percentage of dividing cells—because none of those things seemed to be true—but because the tumor mass itself was a recipient of metastatic cells,” said Dr. Norton.

Proof of Concept

The two researchers tested their hypothesis in a mouse model of cancer and published their results in 2009 in Cell. For one experiment, they chose a non-metastatic breast cancer cell line and an isolated set of daughter cells from that line that had gained the ability over time to metastasize to the lungs.

When the researchers implanted the parent cells in one mammary gland and the metastatic daughter cells in the opposite gland to serve as “donor tumors,” the daughter cells migrated to the lungs and to the tumors that were being formed by the parent cells in the opposite gland, accounting for 5 to 30 percent of the eventual size of the parent tumors. Parent tumors seeded by daughter cells grew faster than parent tumors that were implanted alone without daughter cells in the opposite gland.

The researchers observed this same seeding behavior with daughter cells that metastasize to the bones and brain, and with colon cancer and melanoma cell lines, but they did not see the effect when they transplanted daughter cells that were not metastatic.

In a set of follow-up experiments performed in the laboratory, the researchers showed that cells from primary tumors can attract circulating metastatic tumor cells, and they identified several proteins that likely encourage this migration. They also found that the returning metastatic cells promoted primary tumor growth by releasing proteins that change the tumor’s microenvironment, including blood vessels and immune cells, explained Dr. Massagué in an e-mail.

Clinical Implications of Self-Seeding

This theoretical phenomenon—accelerated tumor growth jump-started by a high rate of tumor cell death—has potential implications for the clinical treatment of cancer. Traditional cytotoxic chemotherapy drugs kill large numbers of rapidly dividing cancer cells, but may not affect cancer stem cells in every tumor type.

“Our model suggests that discouraging migration might provide an alternative means of cancer suppression. Importantly, the results suggest that antimitotic treatments alone, despite killing cancer cells, may actually promote tumor progression if eradication of cancer stem cells cannot be achieved,” wrote Dr. Hahnfeldt and his colleagues in their 2009 paper.

Currently, no anticancer drugs exist that specifically interfere with the process of metastasis, though researchers are actively working on understanding the genetic changes that drive a cancer cell’s ability to break away from a tumor and survive in the blood stream, in the hopes of making metastasis a valid therapeutic target.

And, although the concept of cancer stem cells remains under debate, if self-seeding can be confirmed in cancer patients, what is learned could influence the timing and nature of cancer treatment.

“Some of the things that we do to a tumor—are they inhibiting the process of seeding or are they augmenting the process of seeding?” asked Dr. Norton. “That’s something we don’t know the answer to yet, but it is something we need to seriously consider.” In some cases, removing a primary tumor without first attempting to kill circulating tumor cells may actually encourage distant metastases, as those cells lose their preferred “home” and lodge elsewhere in the body, he explained.  >> Read Complete Article

Preclinical research suggests that patients with a variety of vascular conditions, such as diabetes, hypertension, inflammation, stroke, and heart attack may benefit by increasing their EET levels, because the compounds cause blood vessels to dilate and reduce tissue inflammation and cell death. However, previous work has also demonstrated that EETs make tumor cells grow faster and cause them to migrate and become metastatic.

According to Dipak Panigrahy, M.D., an author on the paper and a research associate at the Dana-Farber/Children’s Hospital Cancer Center, Boston, EETs have a potent stimulatory effect promoting cancer growth and metastasis, a process that could be effectively inhibited using novel antagonists, such as EEZE, which are compounds that interfere with this pathway in mice. EEZE has not been approved for human use, and is only used for research.

“EEZE is structurally similar to EETs, but it blocks the effect of EETs and dramatically slows tumorigenesis,” Panigrahy explained.

Mark Kieran, M.D., Ph.D., another author of this collaborative study and also from Dana-Farber, commented on the importance of the research.

“The identification of an old pathway studied for many years in cardiovascular disease has found a new role in regulating cancer growth and metastasis, the primary causes of cancer related deaths,” he said. “With these findings, opportunities to better understand the underlying mechanisms that drive cancer, and thus the development of effective therapies for their treatment, moves one step closer to a reality.” >> Read Full Article