Archive for the ‘Chemotherapy’ Category

New Combination Therapy For Solid Tumors?

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Posted 18 Feb 2011 — by James Street
Category Chemotherapy, Drug Interactions, Hypoxia, Understanding Cancer

15 Feb 2011

Most, if not all, solid tumors contain regions that are not well oxygenated. Tumor cells in these regions, which are known as hypoxic regions, are usually resistant to the death-inducing effects of chemotherapeutics. But now, Caroline Dive and colleagues, at Manchester University, United Kingdom, have identified a compound (ABT-737) that induces human cancer cells exposed to hypoxic conditions in vitro to undergo a form of cell death known as apoptosis. In addition, cells in hypoxic regions of human tumors xenografted in mice were susceptible to ABT-737-induced apoptotic cell death. As ABT-737 synergized with conventional chemotherapeutic agents in tumor-bearing mice, the authors suggest that such a combination of drugs could improve treatment of solid tumors.

TITLE: Hypoxic human cancer cells are sensitized to BH-3 mimetic-induced apoptosis via downregulation of the Bcl-2 protein Mcl-1

Source:
Ushma Neill
Journal of Clinical Investigation

Patients With Cancer Like Jobs Gain Months From New Therapies

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Posted 26 Jan 2011 — by James Street
Category Chemotherapy, Combination Treatments, Drug Testing, Drugs, experimental treatments, genetic research

January 25, 2011, 12:09 AM EST

By Michelle Fay Cortez and John Lauerman

Jan. 25 (Bloomberg) — Pfizer Inc. and Novartis AG drugs have helped patients with the same cancer as Apple Inc.’s Steve Jobs live longer in recent studies and Stanford University, near Apple’s home base, is testing new drug combinations.

The Apple chief executive officer took a leave of absence in 2004 after saying he had a neuroendocrine tumor, a malignancy that strikes about 3,000 Americans a year. He left in 2009 for a liver transplant, sometimes done when the cancer spreads.

If Jobs’s third leave, announced to employees Jan. 17, means the malignancy is back, his treatment options now include a wave of new drugs that add months on average to survival rates, even as they carry side effects that can include fatigue, diarrhea, vomiting and low blood counts that can spur infection, doctors say. Jobs has already beaten the odds, according to a 2007 study finding that patients with the tumor die an average of three years after diagnosis.

Since then, “there have been advances that might be applicable to his case,” said John Fung, chairman of the Cleveland Clinic’s Digestive Disease Institute, in a telephone interview. “If he has a recurrence, it isn’t the end of the world.” Fung said he hasn’t been involved in Jobs’s case.

Neuroendocrime tumors create a hormone imbalance that can cause the body to improperly process calories, among other effects, according to pancreatica.org, funded by the Cancer Patients Alliance, based in Pacific Grove, California.

Trouble Gaining Weight

The Apple co-founder has had trouble maintaining weight in recent months, and immunosuppressant medications related to the transplant have made him susceptible to colds and the flu, according to a person with direct knowledge of Jobs’s health who requested anonymity because the matter is private.

Steve Dowling, an Apple spokesman, declined to comment beyond a Jan. 17 company statement that excluded details on Jobs’s health.

The leave isn’t necessarily a sign Jobs’s cancer has returned, said Abhinav Humar, clinical director of the transplantation division at the University of Pittsburgh Medical Center in Pennsylvania.

With a demanding drug regimen and scanning for infections or new tumors, “he could just need time out and recuperation,” Humar said in a telephone interview. “It could be that his medical condition isn’t severe, but the average transplant patient doesn’t have the job he does or the physical or psychological pressures he does.”

If the tumors have recurred, though, Jobs may already be on therapy that could include the cancer drug Sutent, made by New York-based Pfizer, or Afinitor, from Basel, Switzerland-based Novartis. Both have prolonged the lives of patients with advanced tumors by months in human trials.

Targeted Therapies

Additionally, Stanford researchers are testing Avastin and Tarceva, medicines made by Basel-based Roche Holding AG, in combination with other drugs. All four are part of an explosion of so-called targeted therapies that attack cancer at the molecular level, holding the promise of turning intractable malignancies into chronic diseases like diabetes or HIV.

Sutent in 2006 became the first treatment simultaneously approved for two malignancies: gastrointestinal stromal tumors, or GIST, and renal cell carcinoma.

The drug works by choking off a tumor’s blood supply. In 30 percent or more of patients, it also carries side effects that can include fatigue, diarrhea, vomiting, high blood pressure and low blood counts that can lead to infection and anemia, according to Chemocare.com, a website funded by the nonprofit Scott Hamilton CARES group.

Survival Time Doubled

Sutent more than doubled the time neuroendocrine tumor patients lived without the cancer’s worsening, to 11.4 months from 5.5 months. Those figures are an average, meaning that some patients receive no benefit from the drug and die quickly, while others may gain years of added life.

The study of 171 patients, reported in a Dec. 2 Pfizer statement, led to the drug’s approval in Europe last month for use against neuroendocrine tumors.

Afinitor, which carries some of the same side effects as Sutent, works by blocking a protein called mTOR that’s needed for some cancers to grow and spread, and is used at a lower dose to prevent rejection of organ transplants.

Patients given Afinitor had no tumor growth for a median of 11 months compared with 4.6 months for those on standard supportive care, and the medicine reduced the risk of the cancer’s spreading by 65 percent, Novartis said in an Oct. 11 statement. The study was dubbed Radiant-3.

Stanford Research

Researchers at Stanford, located near Palo Alto, California, about 20 miles north of Apple’s Cupertino offices, are testing combinations that include pertuzumab, which neutralizes the HER-2 protein that promotes tumors; Tarceva, which blocks a protein called epidermal growth factor that helps cancer cells spread; and Avastin, which hinders a protein needed by the tumor to produce new blood vessels.

Pamela Kunz, an assistant professor of oncology at Stanford, is involved in two of the studies. She said she isn’t working with Jobs and that she couldn’t answer questions about him or his case.

One trial Kunz is working on is looking at 40 patients treated with Avastin, Roche’s Xeloda and the cancer drug oxaliplatin, she said. Since the study began five years ago, 60 percent of the patients had slowed growth of their tumors and 20 percent had some tumor shrinkage.

The results were presented last year at a meeting of the American Society of Clinical Oncology, Kunz said.

Second Study

A second Stanford study combines the experimental drug pertuzumab with Tarceva, Kunz said. The effects of the drug combination have been difficult to assess so far because only four patients have been treated, and some patients have suffered side effects such as severe rash and diarrhea.

Kunz said she’s still trying to determine how to follow up on the results of the three-drug study with Avastin.

“If we were going to do larger study, it would have to be involve more centers because the patient population for this disease is so small,” she said yesterday in a telephone interview. “These trials take a long time.”

James Yao, deputy chairman of gastrointestinal medical oncology at the University of Texas’s MD Anderson Cancer Center in Houston, led the 2007 study, published in the Annals of Surgical Oncology, that found a median survival of 38 months for 1,310 patients with neuroendocrine tumors. The range of the study ran from 23 months when the disease had spread to 10 years when it hadn’t.

Liver Transplants

Other researchers have also studied the success of liver transplants as a treatment for neuroendocrine tumors. In 2005, David Metz, associate chief of gastroenterology at the University of Pennsylvania in Philadelphia, published an analysis in the World Journal of Gastroenterology that suggested 60 percent or fewer of patients who underwent transplants for this purpose survive an average of 5 years.

The information, taken from individual medical centers, is of varying quality and hard to interpret, Metz said. The chance of survival may be greater today, he said.

Preliminary data collected on 47 transplant patients by Linda Sher, a surgeon at the University of Southern California in Los Angeles, support Metz’s findings.

Fourteen of 15 patients whose original tumors were removed before the transplant were still alive in 2009. Eight had lived more than three years, and four had lived five years or longer. One had lived about 15 years, she reported.

Sher is collecting data from more patients who have undergone the procedure to determine which cases are most likely to benefit, she said in a telephone interview.

Memphis Transplant

Jobs’s transplant was performed by James Eason in his transplant unit at Methodist University Hospital in Memphis, Tennessee.

Eason, who declined to comment through a spokesman last week, said after the surgery in 2009 that he performs the procedure only when he is certain he can eliminate all the spreading cancer.

–With assistance from Adam Satariano in San Francisco. Editors: Jeffrey Tannenbaum, Donna Alvarado.

To contact the reporter on this story: Michelle Fay Cortez in Minneapolis at mcortez@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

CLINICAL AND PHARMACOKINETIC EVIDENCE OF A LIFE-THREATENING INTERACTION BETWEEN METHOTREXATE AND KETOPROFEN

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Posted 21 Jan 2011 — by James Street
Category Chemotherapy, Drug Interactions, Mouse Osteosarcoma Studies

References and further reading may be available for this article. To view references and further reading you must purchase this article.

Antoine Thyss, Johanna Kubar, Gerard Milano, Moise Namer and Maurice Schneider

Centre Antoine-Lacassagne, Nice, France

Available online 11 September 2003.

Abstract

Co-administration of ketoprofen was found in 4 of 118 cycles of high-dose methotrexate (MTX) analysed retrospectively in thirty-six patients. All 4 cycles were characterised by severe MTX toxicity, which was fatal in three cases. Simultaneous administration of ketoprofen was associated with prolonged and striking enhancement of serum MTX levels. There were no abnormalities in MTX kinetics or evidence of MTX toxicity when ketoprofen was given at least 12 h after completion of high-dose MTX infusion. The kidney may be the site of drug interaction. This high-risk association between MTX toxicity and ketoprofen may also apply to other non-steroidal anti-inflammatory drugs.
Article Outline

• References

The Lancet
Volume 327, Issue 8475, 1 February 1986, Pages 256-258

Mifamurtide for the treatment of nonmetastatic osteosarcoma

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Posted 14 Jan 2011 — by James Street
Category Chemotherapy, Human osteosarcoma research, Local Recurrence, Lung Metastases, Metastases, Osteosarcoma Outcomes

Ando K, Mori K, Corradini N, Redini F, Heymann D.

Shiga University of Medical Science, Department of Orthopaedic Surgery, Otsu, Shiga, 520-2192, Japan +81 77 548 2252 ; +81 77 548 2254 ; ando-ko@mx.scn.tv.
Abstract

Introduction: The standard treatment for osteosarcoma requires both macroscopic surgical wide resection and postoperative multi-drug chemotherapy in neoadjuvant and adjuvant settings. However, the 5-year event-free survival has remained at a plateau of 60 – 70% of patients with nonmetastatic osteosarcoma for more than 30 years. Areas covered: Mifamurtide (liposomal muramyl tripeptide phosphatidylethanolamine; L-MTP-PE) is a new agent. L-MTP-PE is a nonspecific immunomodulator, which is a synthetic analog of a component of bacterial cell walls. L-MTP-PE activates macrophages and monocytes as a potent activator of immune response in addition to standard chemotherapy. It also improves the overall survival from 70 to 78% and results in a one-third reduction in the risk of death from osteosarcoma. This review summarizes the most recent findings about L-MTP-PE and its therapeutic application for nonmetastatic osteosarcoma. Expert opinion: Recently, L-MTP-PE has been approved in Europe for the treatment of nonmetastatic osteosarcoma with chemotherapy. L-MTP-PE in combination with traditional treatment is expected to go mainstream and to be beneficial for patients with osteosarcoma. Information about potential benefit regarding mifamurtide use in the neoadjuvant setting (i.e., before surgery) and/or usefulness of L-MTP-PE in metastatic in relapsed and metastatic osteosarcoma requires analysis of expanded access and/or future clinical trials of L-MTP-PE in high-burden and low-burden situations.

PMID: 21226638 [PubMed - in process]

Scientists Target Tumors’ Most Resilient Cells

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Posted 21 Dec 2010 — by James Street
Category Chemotherapy, Stem Cell Research

By RON WINSLOW

In laboratories around the world, researchers trying to understand why cancer is such a tenacious foe are probing a component of tumors known as cancer stem cells.

Scientists have identified in recent years a subset of cells in a variety of cancers that appear resistant to conventional treatments such as chemotherapy and radiation. A growing number of researchers believe these hard-to-kill cells are a major reason why cancer treatments often fail. In addition, the theory goes, these cells drive metastasis—the deadly spread of tumor cells beyond their site of origin to other organs. Many scientists call them cancer stem cells because, in contrast to most cancer cells, they can self-renew.

Now, some researchers are seeking to identify drugs that specifically target cancer stem cells. The premise is that combining such agents in a one-two punch with standard treatments might more effectively obliterate tumors and produce long-lasting results for patients.

Cancer stem cells present “a quandary for the oncologist,” says Robert Weinberg, a cancer researcher at Massachusetts Institute of Technology. With chemotherapy, “the tumor may shrink dramatically in size and the non-stem cells may be effectively killed.” But a high proportion of the surviving cells are cancer stem cells, he says. “They can live and persist and regrow the tumor.”

Dr. Weinberg and colleagues at MIT’s Whitehead Institute are collaborating with researcher Eric Lander at the Broad Institute of MIT and Harvard University in one effort to hunt for potential cancer stem cell killers. Key to the effort is a strategy for screening chemical compounds that Dr. Weinberg says was devised principally by Piyush Gupta, a researcher who has worked in the labs of both Dr. Weinberg and Dr. Lander.

A Cancer Stem Cell Primer

Q. What is a cancer stem cell?

A. It is a tumor cell capable of self-renewing and seeding the growth of other tumors.

Q. How were cancer stem cells discovered?

A. Scientists transplanted tumor cells in mice. Some caused the mice to get cancer, others didn’t.

Q. Why are they important?

A. Studies show cancer stem cells often survive chemotherapy and other treatments that kill most other tumor cells. The surviving cells can then cause a more aggressive cancer to come back and spread.

Q. Can a cancer stem cell become any kind of cancer?

A. Breast, colon, lung and other cancers appear to have their own specific stem cells, which share some molecular traits in common.

Q. Can cancer stem cells be treated?

A. Academic researchers and some companies are developing drugs they hope will kill cancer stem cells specifically. A likely strategy would be to combine such treatments with conventional therapies to attack both regular tumor cells and cancer stem cells.

Q. What are the caveats?

A. Cancer is complex. Many assumptions about cancer stem cells remain unproven.

The technique was described in a paper last year in the journal Cell. Last month, a company called Verastem was launched to use the approach to identify promising drug candidates and advance them to human studies. All three scientists are on the company’s scientific advisory board.

But much about cancer stem cells—where they come from, how they affect development of disease and whether they can be effectively attacked with treatment—is unclear. Even the term “cancer stem cell” is a source of contention among scientists.

“People are still trying to define exactly what a cancer stem cell is,” says Bert Vogelstein, a cancer researcher at Johns Hopkins Medical Institutions.

One way cancer cells are believed to turn aggressive is by reactivating cellular-growth programs involved in normal embryonic development that usually are dormant in adult cells. The cancer cells exploit those programs to become invasive, metastatic and thus life-threatening. As part of the process, certain regular cancer cells take on properties that enable them to split off from the tumor and invade other tissues.

“It’s not as if cancer cells invent this program,” Dr. Weinberg says. “They reach back into their early origins in the embryo, turning on genes and behavioral programs that in adult cells are usually shut down.”

Dr. Gupta was a doctoral student working with Dr. Weinberg when the lab figured out how to make human breast-cancer cells aggressive by activating one of these early embryonic programs. They found the resulting invasive cells shared many molecular traits in common with stem cells. The experiment also yielded a way to make large numbers of cancer stem cells, an advantage because cancer stem cells generally make up only a tiny fraction of the cells in most tumor types, making research with them difficult. Dr. Gupta figured that the peculiar behavior of cancer stem cells might make them especially vulnerable to certain drugs, Dr. Weinberg says.

As a post-doctoral fellow in Dr. Lander’s lab, Dr. Gupta took advantage of the ability to make large numbers of the cells to screen some 16,000 compounds for toxicity specifically against breast-cancer stem cells.

He came up with four hits, including an antibiotic called salinomycin that is given to animals such as chickens. In tests against breast-cancer cells in mice, salinomycin had little effect on conventional tumor cells. But it was 100 times as effective as the widely used breast-cancer treatment paclitaxel in killing cancer stem cells, according to the paper in Cell last year.

The publication drew the attention of biotech investor Christoph Westphal, whose Longwood Founders Fund led the $16 million financing that resulted in the launch of Verastem. He hopes the work will result in at least one compound reaching human studies within two or three years.

Dr. Weinberg says if the approach works in breast cancer, it likely holds promise for other solid tumors such as colon and prostate cancers as well, though molecular markers of the stem cells may differ depending on tumor type.

The collaboration involving Dr. Weinberg and Dr. Lander brings together two prominent researchers. Over more than three decades, Dr. Weinberg’s lab has uncovered some of cancer’s fundamental secrets. In 1982, for instance, he and his colleagues discovered the first human cancer-causing gene.

Dr. Lander, a mathematician by training, was a leader of the publicly funded effort to decode the human genome. His lab uses powerful sequencing machines and robotic technology to investigate the genetic and molecular mechanisms of disease.

The two scientists have co-taught an introductory biology course at MIT for more than a decade. Their labs are steps away from each other. But they have rarely collaborated on research. Dr. Weinberg credits Dr. Gupta with bringing the two labs together over cancer stem cells. (Neither Dr. Lander nor Dr. Gupta was available to comment.)

Still, finding a successful drug isn’t assured.

Geoff Wahl, a researcher at Salk Institute, La Jolla, Calif., says resistance of tumor cells to conventional treatment has multiple causes. “It doesn’t mean the answer to resistance is treating the stem cell.”

Jonathan Kurie, an oncologist at M.D. Anderson Cancer Center, Houston, calls pursuit of cancer stem cell killing drugs a “good first step.” But “if they’re particularly hard to kill [with chemo] then trying to kill them” with other therapies may not be the best approach.

It may be more effective, though admittedly trickier, to interfere with their ability to invade other organs, he says.

Dr. Weinberg acknowledges the uncertainty. “Some aspects of the cancer-stem-cell model remain to be proven,” he says. “But what we’re talking about does make sense.”

Write to Ron Winslow at ron.winslow@wsj.com

Wall Street Journal

Invention Could Improve Cancer Drug Delivery, Lessen Harmful Effects of Chemotherapy

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Posted 20 Dec 2010 — by James Street
Category antiangiogenesis, Chemotherapy, experimental treatments, Molecular, NanoTechnology

Xenia KachurXenia Kachur, a graduate student in the Biomedical Engineering Graduate Interdisciplinary Program at the UA, is working on a project to deliver chemotherapeutic drugs to cancer tissues without harming healthy body cells. (Photo by Beatriz Verdugo/UANews)

Sarah LeungSarah Leung, a fourth-year graduate student, is also working in the Romanowski lab. (Photo by Beatriz Verdugo/UANews)

Xenia and SarahXenia Kachur and Sarah Leung are both graduate students in the Biomedical Engineering Graduate Interdisciplinary Research Program at the UA. (Photo by Beatriz Verdugo/UANews)

An invention by UA researchers may provide a way to deliver chemotherapeutic drugs to cancer tissues in controlled doses without harming healthy body cells.

By Shelley Littin, NASA Space Grant intern, University Communications, December 20, 2010

University of Arizona researchers may have found a way to deliver chemotherapeutic drugs to cancer tissues in controlled doses without harming healthy body cells.

If successful, the invention of gold-coated liposomes could make chemotherapy more effective to destroy cancer cells and alleviate the harmful side effects that can result from the treatment.

The invention by Marek Romanowski, an associate professor of biomedical engineering in the UA College of Engineering and a member of the BIO5 Institute and the Arizona Cancer Center, and his lab team doesn’t have a silver lining. Better: It has a lining of gold. The secret to non-invasively controlling the release of chemotherapeutic drugs lies in nano-scale capsules made of lipids and coated with a fine layer of gold.

Chemotherapeutic drugs are sometimes encased in small capsules called liposomes, which are made of organic lipids that are already present in human cells. The lipid encasing keeps the body’s immune system from attacking the foreign molecule before it can deliver the drug.

Once released into the bloodstream, drug-carrying liposomes accumulate around a cancer tumor because of a property known as leaky vasculature: Tumor cells have extra openings to blood vessels to take in nutrients carried in the bloodstream, usually because they are trying to grow more quickly than normal cells. The extra blood flow means that more nutrients, and also more liposomes, are likely to accumulate in the tumor cells where they eventually break down and release the drug into the cells, leading to cell death.

The highly toxic drugs used for chemotherapy destroy cancer cells, but with no way to discriminate between cell types, they can also damage healthy cells. This damage to the body’s normal, healthy cells leads to the side effects normally associated with chemotherapy treatments: anemia, hair loss, vomiting – as cells that make up stomach lining are destroyed – and nausea, among others.

Keys in a lock

To better target cancer cells, the UA team attached liposomes to signal molecules called ligands, which interact with specific cell receptors like keys in a lock.

“It all depends on the disease that we’re targeting, but in the case of tumor cells, they over-express certain receptors for several reasons. One is tumor cells are proliferating very quickly, and so they’re over-expressing a lot of nutrient receptors because they want to divide faster,” said Xenia Kachur, a third-year graduate student in the Biomedical Engineering Graduate Interdisciplinary Program, or GIDP. The extra receptors make the liposomes more likely to latch onto and get inside tumor cells than normal cells.

As they degrade, liposomes release drugs bit-by-bit in an uncontrolled fashion, which may not effectively destroy tumor cells. Said Sarah Leung, a fourth-year graduate student in the biomedical engineering GIDP who also is in the Romanowski lab: “There’s a particular concentration at which you have optimal results, so below that you don’t have enough of the drug to get a good response, and above that it might be even more toxic.”

The new invention could allow doctors to control the amount of drug released at a time, and to release the drug only in the tumor region, thereby protecting healthy cells from damage caused by the drug. This is where the gold lining comes in.

Drugs coated in gold

“A property of gold is that it can convert near infrared light into heat,” said Kachur. “By putting gold on the surface of these liposomes, we can then put in a stimulus such as near-infrared light. The gold converts the light into heat, the heat causes the liposome to become leaky, and then whatever’s really concentrated inside can diffuse out through the leaky liposome.”

“Infrared light penetrates the deepest through the body because it interacts the least with most tissues, and it also prevents a lot of the heating that your body might [otherwise] experience,” said Kachur.

The theory goes that the amount of infrared light can be varied to control the amount of drug that is released from the gold-coated liposomes.

“By using more or less light, you can release more or less of the drug and time the responses as well, so when you trigger light, some drug will leak, you can trigger it again and have more drug leak, or you can wait a little while, let the drug disperse, do its thing, then trigger it again. It allows for a lot more freedom with the release process,” said Leung. “By having this very triggered response you can hit that therapeutic window.”

Despite increased blood-flow to tumor cells and the key-in-lock action of the ligands, some liposomes may still end up inside healthy cells. In that case, the gold-coating could potentially act to prevent release of the toxic drug to the healthy cells.

By selectively shining the infrared light only in the tumor region, doctors could make sure only liposomes in the tumor region are able to release the drug.

“Once you know where the tumors are, you can go ahead and point your light source toward those areas. Whatever else is left will leave the body or may be slowly released, but not to as high or as toxic of levels as it would be if you just injected the drug systemically,” said Leung.

The invention has another bonus: “The gold-coated liposome is biodegradable, which is one of the best parts of our system,” said Leung. Currently there are no approved chemotherapeutic treatments that allow the gold nanostructures to be eliminated from the body by the body’s own mechanisms, said Leung.

Kidneys, the organs that normally filter waste molecules out of the blood, have a limit as to the size of molecule they can filter. “Because of the size it degrades into, our system should be clearable via the kidney, which is really unique,” said Leung.

There still are many steps to take to test the invention before it could be used in cancer therapy. But if successful, gold-coated liposomes could provide a method to target chemotherapeutic drugs to cancer cells, non-invasively trigger the drugs’ release using infrared light and provide a way for the body naturally to filter the drug from the bloodstream.

One day, cancer patients could potentially receive chemotherapy treatments with confidence that the drugs will effectively destroy cancer cells, and without fear of suffering any harmful side effects.

This research is funded by grants from the National Institutes of Health and the National Science Foundation.

Light-sensitive drug to treat prostate cancer

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Posted 18 Dec 2010 — by James Street
Category Chemotherapy, Drugs, Light-sensitive, Prostate Cancer

Contact: Brian Murphy
brian.murphy@ualberta.ca
780-492-6041
University of Alberta
Master’s student takes top thesis competition while tackling prostate cancer research

The future of cancer treatment and a University of Alberta graduate student’s personal career prospects are looking bright. Weiyang Liu beat competitors from 80 of the best university graduate schools in western North America with his master’s thesis on the use of a light-sensitive drug to treat prostate cancer.

Liu, a U of A electrical engineering student, had his research reviewed internally at the U of A and was put forward as the university’s sole entry into the annual master’s thesis competition sponsored by the Western Association of Graduate Schools, which represents some 80 university graduate schools located in western Canada and the United States. He is part of the university’s interdisciplinary team developing a two-technology treatment that specifically targets a cancerous prostate gland.

Liu says the combination of drug treatment and the fibre-optics system could one day replace the long-standing prostate cancer treatments alternatives, chemotherapy or surgery. “Our prostate cancer drug is injected into a patient, but only begins killing cells when it’s activated or turned on by laser light, which is guided by tiny fibre-optic cables that have been inserted into the patient’s prostate gland,” said Liu. “This delivers the cancer treatment right to the prostate, unlike chemotherapy, which attacks the whole body.”

And, unlike chemotherapy, Liu says the light-activated drug produces a natural cell death, which breaks down the cancerous tissue in the prostate gland for normal absorption of dead cells by the patient’s body. Statistics show that one in six Canadian men will require prostate cancer treatment. In his award-winning thesis, Liu also discussed the patient’s fallout from surgical removal of the prostate. The surgical procedure can leave patients incontinent and impotent. “The high cost of surgery and the hospital stay can be avoided with photo-dynamic therapy,” he says.

The drug component of the new treatment is already in clinical trials and the U of A team is hopeful that the fibre-optic light therapy will be added to human testing sometime next year. Liu and his supervising U of A professors, John Tulip and Ronald Moore, will travel to San Diego in March to receive the award. “I’m very proud that we won, when you consider the competition in western North America. We were up against large California schools like UCLA, CalTech and UC Berkeley,” said Liu.

Nanoparticles deliver one-two therapeutic punch to kill tumor cells

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Posted 17 Dec 2010 — by James Street
Category Chemotherapy, NanoTechnology

(Nanowerk News) The standard approach to cancer therapy today is to mix and match chemotherapy drugs in order to attack tumors in multiple ways. Now, two separate teams of investigators have demonstrated that using nanoparticles to deliver multiple drugs simultaneously can produce a synergistic effect that boosts the cell-killing ability of both drugs. In one study, a team of investigators at Northwestern University has shown that they can combine two powerful but extremely toxic anticancer agents – cisplatin and doxorubicin – in one polymer nanoparticle, producing a substantial boost in their ability of the combination to destroy tumors. In addition, the two-in-one nanoparticle reduces the amount of both drugs needed to kill cancer cells, which presumably would reduce the toxic side effects associated with these drugs. SonBinh Nguyen and Thomas O’Halloran led this study, which was published in the Journal of the American Chemical Society (“Polymer-Caged Nanobins for Synergistic Cisplatin-Doxorubicin Combination Chemotherapy”). Dr. O’Halloran is the co-principal investigator of one of 12 Cancer Nanotechnology Platform Partnerships funded by the National Cancer Institute Alliance for Nanotechnology in Cancer. He is also a member of the Northwestern University Center for Cancer Nanotechnology Excellence (CCNE), which is also part of the Alliance for Nanotechnology in Cancer. Though originally designed to carry arsenic trioxide to solid tumors, the nanoparticles used in this study are proving to be quite versatile in their ability to ferry a wide range of cargos to malignancies. In this study, the investigators wanted to see if delivering two drugs in one nanoparticle offered any advantages of delivering them without the nanoparticle or in separate nanoparticles. The nanoparticles, which the researchers call nanobins, are made by encasing a liposome inside a pH-responsive polymer cage. In this case, doxorubicin is entrapped within the liposome’s core, while cisplatin was entrapped in the polymer cage. In an initial set of experiments, the investigators determined that a 5 to 1 ratio of cisplatin to doxorubicin was the most effective at treating ovarian tumors when the two drugs were combined in the same nanoparticle. When the two drugs were administered at this ratio but with each in its own nanoparticle, the combination was not only less effective at killing malignant cells, but the two drugs appeared to be interfering with each other, a phenomenon often observed in clinical practice. Administering the two drugs in the same nanoparticle ensures that the drugs are hitting their intracellular targets at the same time, which is what likely leads to the synergism observed in this study. Meanwhile, Mansoor Amiji and Zhenfeng Duan, co-principle investigators of the Cancer Nanotechnology Platform Partnership at Northeastern University, have shown that a different type of polymer nanoparticle can also deliver two anticancer agents simultaneously and as a result can kill cancer cells that have become resistant to drug therapy. In this case, the researchers synthesized biocompatible polymer nanoparticles that entrapped paclitaxel and lonidamine and that targeted the epidermal growth factor receptor (EGFR) that is overexpressed on highly aggressive tumors. When added to tumor cells growing in culture, the nanoparticle containing both drugs was far more effective at killing the drug-resistance cells than when the two drugs were co-administered in separate nanoparticles. The investigators reported their findings in the journal Molecular Pharmaceutics (“Development of EGFR-Targeted Polymer Blend Nanocarriers for Combination Paclitaxel/Lonidamine Delivery To Treat Multi-Drug Resistance in Human Breast and Ovarian Tumor Cells”). In a separate set of experiments, the results of which were published in the journal Angewandte Chemie International Edition (“Modular Polymer-Caged Nanobins as a Theranostic Platform with Enhanced Magnetic Resonance Relaxivity and pH-Responsive Drug Release”), Drs. Nguyen and O’Halloran, joined by Thomas Meade, another member of the Northwestern CCNE, demonstrated that nanobins can also co-deliver a therapeutic and magnetic resonance imaging agent to tumors. In this study, the researchers loaded the anticancer agent gemcitabine into the nanobin’s core and added a gadolinium magnetic resonance contrast agent to the nanobin’s surface. When added to mouse tumor cells, the nanobins were taken up rapidly and the nanobins were clearly visible in magnetic resonance images. In addition, the nanoparticles released their gemcitabine payload once the nanobins were taken up by the cultured cells.

Source: National Cancer Institute

Cancer Patients Should Avoid Listeria Containing Cheese Products

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Posted 17 Dec 2010 — by James Street
Category Chemotherapy

Submitted by Olivia Conroy on Thu, 12/16/2010 – 09:02

Public health experts have extended their warning on avoiding soft cheeses from pregnant women to cancer patients as the products have been suspected of being tainted with listeria bacteria.

The Health Protection Agency conducted a research, which revealed that the cancer patients are more vulnerable to getting affected with food poisoning caused due to listeria, bacteria that can be found in foods like soft cheese and pate.

Those receiving chemotherapy have been specifically warned by Cancer Research UK to remain cautious.

Listeria is a condition in which one develops serious illness due to consumption of food containing the bacterium Listeria monocytogenes. If pregnant women get affected with it, they could suffer miscarriage. The infection could also cause blood poisoning or meningitis in people having feeble immunity.

The researchers analyzed 1,413 people in England (not including pregnant women) who suffered from listeria between 1999 and 2009. Majority of them were already affected with underlying conditions and thus had more chances of getting listeria infection.

It was found that cancer patients were five times more likely to catch listeria as compared to other conditions such as diabetes. Those having cancers of the blood were at the highest risk threshold.

“Our research has shown that those receiving cancer treatment or suffering from a variety of conditions, including diabetes, kidney or liver disease, should be offered appropriate health advice on how to avoid listeria”, said Dr. Bob Adak of the HPA.

Killing Drug-Resistant Melanoma Requires Combination Therapy

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Posted 14 Dec 2010 — by James Street
Category Chemotherapy, Combination Treatments

Three melanoma tumor spheroids, resistant to BRAF inhibitors, in a three-dimensional cell culture. Here, the difference between untreated living cells (green) and dead cells (blue) indicate success of a combination of MEK and PI3Ki inhibitors in killing resistant melanoma. (Credit: James Hayden/The Wistar Institute)

ScienceDaily (Dec. 13, 2010) — This past summer saw a revolution in melanoma therapy. Patients whose melanoma lesions contain a mutation in the BRAF gene were successfully treated with a BRAF-specific inhibitor, PLX4032. Reports of the drug trial described shrinking tumors and improved health. Yet seven months after therapy began the tumors returned and resumed growing. Now, scientists at The Wistar Institute explain why: the tumor learns to signal around the blocked gene by adjusting its molecular wiring. They also show how to overcome resistance by simultaneously targeting multiple signaling pathways.

The researchers see this as further evidence that some cancers must be treated with multiple targeted drugs at the outset of treatment. Their findings are published in the December 14 issue of the journal Cancer Cell.

“The evidence suggests that targeting mutant BRAF can kill cancer cells, but it is not enough by itself to finish off melanoma,” said Meenhard Herlyn, D.V.M., D.Sc., director of The Wistar Institute Melanoma Research Center and leader of Wistar’s Molecular and Cellular Oncogenesis program. “The good news is that drugs are being developed to work in combination with BRAF inhibitors, which our data clearly shows is our best option if we intend to beat advanced melanoma.”

Melanoma is the deadliest, most aggressive form of skin cancer. While surgical treatment of early melanoma leads to 90 percent cure rates, advanced melanoma is notoriously resistant to chemotherapy and has a tendency to metastasize, or spread, throughout the body. According to the World Health Organization, cases of the disease continue to rise, which has helped spur research into therapies such as BRAF inhibitors.

To study how melanoma responds to BRAF inhibitors, the Herlyn lab took melanoma cells with the BRAF mutation and tested them against a variety of anti-mutant BRAF drugs. When exposed to the drugs, the cells died off dramatically only to grow back again. In fact, cells that became resistant to one type of BRAF drug became resistant to all of them, which suggests that the cells were biochemically “rewired” in such a way that they no longer needed BRAF to form tumors.

“Cells are complex machines that work, essentially, through chains of biochemical reactions that we refer to as signaling pathways,” said Jessie Villanueva, Ph.D., senior author on the study and staff scientist in the Herlyn laboratory.

“Knocking out mutant BRAF shuts a major pathway down, but if some cells can use an alternate pathway, then they can survive.”

To find out which alternate pathways the drug-resistant cells use, Villanueva and her colleagues looked for signs of increased activation among proteins along the pathways BRAF uses, as well as other pathways.

Their hunt turned up two paths that worked together to aid survival. First, they found that resistant cells used a protein similar to BRAF to carry the signal down the chain. Second, they found these cells received an additional boost from the IGF-1 receptor, a protein that sits on the surface of cells and sends signals that prevent cells from being killed. The resistant cells re-route the signal around BRAF by switching to an alternate protein (CRAF or ARAF), which promotes tumor cell growth, while IGF-1R signaling promotes survival of the resistant cells.

Fortunately, there are a number compounds in clinical development that could block signals along both these pathways. So-called MEK inhibitors target a protein along the same pathway as BRAF, and IGF-1 receptor inhibitors (and inhibitors of P13K, a protein that can be activated by the IGF-1 receptor pathway) block the cancer-enabling survival signal. To test these drug combinations in the BRAF-inhibitor resistant cells, the Herlyn laboratory used a tool they developed to simulate the real-world environment of human cells: 3-D melanoma tumor spheroids. Their 3-D tissue cultures allow melanoma cells to grow in all directions, much like a new melanoma tumor would grow after metastasis. As predicted, a combination of these two inhibitors killed BRAF-resistant melanoma cells in the Wistar 3-D model.

Moreover, the Herlyn laboratory confirmed in tissue samples from patients in the PLX4032 trial — taken both before treatment and after they developed resistance — that an increased expression of the IGF-1 receptor is associated with resistance to BRAF inhibitors. None of the laboratory-generated cell lines or the post-relapse patient’s tumor samples analyzed had new mutations in the BRAF, NRAS, or c-Kit genes.

Additionally, the researchers noted an association between the loss of a tumor suppressor called PTEN, and resistance to BRAF inhibitors in melanoma cell lines. The scientists found that the relapsed tumor of one patient included in the study lost the PTEN gene, even though it was present before treatment. These findings suggest that loss of PTEN could be an additional way that melanoma cells gain resistance to BRAF inhibitors. The Wistar group continues to investigate these and other mechanisms of resistance, as they expect that several will likely arise given the heterogeneous nature of melanoma.

“Tumors are efficient engines of evolution — they are going to find a way around most treatments, so we want to kill all the malignant cells from the very beginning,” said Villanueva. “By targeting both pathways simultaneously you hit these cells with two punches from which they cannot recover.”

“If you do this at the outset of treatment, we reason, it will prevent melanoma survival and hopefully improve patient outcomes,” Villanueva added.

Support for this study was provided by grants from the National Cancer Institute and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

Wistar co-authors in this study include Adina Vultur, Ph.D.; John T. Lee, Ph.D.; Rajasekharan Somasundaram, Ph.D.; Mizuho Fukunaga-Kalabis, M.D., Ph.D.; Angela K. Cipolla; James E. Hayden; and Ademi E. Santiago-Walker, Ph.D. University of Pennsylvania School of Medicine co-authors include Katherine L. Nathanson, M.D.; Xiaowei Xu, M.D., Ph.D.; Phyllis A. Gimotty, Ph.D.; Bradley Wubbenhorst; Richard Letrero; Kurt D’Andrea; and Anitha Pushparajan. Other authors included Grant A. McArthur, M.B., B.S., Ph.D.; and Damien Kee, MBBS, FRACP, of the Peter MacCallum Cancer Centre in Victoria, Australia; Jeffrey A. Sosman, M.D., and Kimberly Dahlman Brown of the Vanderbilt University Medical Center; and Sylvie Laquerre, Ph.D., of GlaxoSmithKline’s division of Oncology Biology in Collegeville, Pa.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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