Monthly Archives: April 2006

AstraZeneca and Abraxis exchange drug programs

  • 4/29/2006
  • London, UK
  • Tom Neilson
  • Pharmaceutical Business Review Online (www.pharmaceutical-business-review.com)

AstraZeneca is to pay $200 million for rights to co-promote in the US Abraxane, a breast cancer drug developed by Abraxis BioScience. Meanwhile, the Anglo-Swedish pharmaceutical company’s branded anesthetic and analgesic products have been acquired by Abraxis for $350 million.

Abraxane, approved by the FDA in January 2005, achieved sales of $134 million in its first 11 months on the market.

The drug is currently in various stages of development for the treatment of a number of other cancers including first-line metastatic breast and non-small cell lung, adjuvant breast, neo-adjuvant breast, malignant melanoma, ovarian, prostate, pancreatic, gastric, and head and neck cancers.

The anesthetic and analgesic products acquired by Abraxis encompass over 100 dosage forms and include the leading branded anesthetic agent, Diprivan, and a proprietary Naropin, as well as a comprehensive suite of local anesthetics including EMLA (eutectic mixture of lidocaine and prilocaine), Xylocaine, Polocaine, Nesacaine, Sensorcaine, and Astramorph.

“This deal gives AstraZeneca access to the key US chemotherapy market. Abraxane brings significant benefits to cancer patients over existing therapies and complements and extends our oncology product portfolio in the US,” said Tony Zook, president and CEO of AstraZeneca US. “At the same time Abraxis BioScience is acquiring a strong anesthetic and analgesic portfolio which enhances their market leading injectable drug portfolio in the US.”

April, 2006|Archive|

Biocon collaborator gets mktg nod for head,neck cancer drug

  • 4/29/2006
  • Mumbai, India
  • staff
  • MoneyControl.com

Scientists in this brand new facility built by Biocon are an excited lot. That’s because Biocon’s collaborator, CIMAB has just received the marketing approval for a revolutionary treatment for head and neck cancer. The fast track approvals are obtained for select countries like Columbia, China, Cuba and Argentina.

The intravenous injectible drug coded H-R3 is a high-end biotech discovery that effectively blocks the epidermal growth factor receptors, a substance that is responsible for the growth of cancer cells. With almost 600 patients clearing the safety and efficacy data, this drug may see quick acceptance among patients with head and neck cancer.

With more marketing approvals for the drug expected from European regulatory agencies soon, Biocon chairperson Kiran Mazumdar Shaw expects due marketing permissions from India too. The pricing, she says, will be affordable to the Indian population.

Biocon scientists say that the drug has significant advantages over its rivals in terms of localisation on points, where the cancer cell density is high. However, with global majors like Genentech working on more sophisticated monoclonal antibodies, this appears to be an exciting opportunities.

Biocon may soon become the first ever Indian company to have its own molecule in the global market.

April, 2006|Archive|

Phase III Trial of an Emulsion Containing Trolamine for the Prevention of Radiation Dermatitis in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck: Results of Radiation Therapy Oncology Group Trial 99-13

  • 4/29/2006
  • Alexandria, VA
  • Elizabeth A. Elliott et al.
  • Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2092-2097

Purpose:
This multicentered phase III trial was designed to compare an emulsion containing trolamine against the usual supportive care within each participating institution for patients with head and neck cancer undergoing radiation therapy.

Patients and Methods:
Patients with biopsy-proven squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to one of the following treatments: prophylactic trolamine emulsion, interventional trolamine emulsion, or declared institutional preference. The primary outcome was the reduction in grade 2 or higher skin toxicity, as per National Cancer Institute Common Toxicity Criteria version 2.0. Secondary outcomes included patient-reported quality of life (QOL).

Results:
From October 2000 to April 2002, 547 patients from 51 institutions were entered onto the trial. The average age was 59 years. Patients were predominately male (79%) and most continued to use tobacco products (52%). The rates of grade 2 or higher radiation dermatitis were 79%, 77%, and 79% in the prophylactic, interventional, and institutional preference arms of the study, respectively. No significant differences in QOL were found.

Conclusion:
The results of this trial demonstrate no advantage for the use of trolamine in reducing the incidence of grade 2 or higher radiation dermatitis or improving patient-reported QOL. The use of 15 different local standards of care highlights the need to continue research that will result in evidence-based recommendations to reduce the burden of radiation dermatitis.

Authors:
Elizabeth A. Elliott, James R. Wright, R. Suzanne Swann, Felix Nguyen-Tân, Cristiane Takita, M. Kara Bucci, Adam S. Garden, Harold Kim, Eugen B. Hug, Janice Ryu, Michael Greenberg, Jerrold P. Saxton, Kian Ang, Lawrence Berk

Authors’ affiliations:
From the Juravinski Cancer Centre at Hamilton Health Sciences; Department of Medicine, McMaster University, Hamilton, Ontario; Notre Dame Hospital, Montréal, Quebéc, Canada; Radiation Therapy Oncology Group, Philadelphia; Dale and Frances Hughes Cancer Center, Pocono Medical Center, East Stroudsburg, PA; University of Miami, Miami, FL; University of California San Francisco Comprehensive Cancer Center, San Francisco; University of California Davis Medical Center, Davis, CA; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Wayne State University, Gershenson Radiation Oncology Center, Detroit, MI; Dartmouth Hitchcock Medical Center, Lebanon, NH; Cleveland Clinic Foundation, Cleveland; and Columbus Community Clinical Oncology Program, Columbus, OH

April, 2006|Archive|

HPV Vaccine and the Religious Right

  • 4/27/2006
  • San Mateo, CA
  • staff
  • ProgressiveU (www.progressiveu.org)

The American Cancer Society says that every year in the United States, an estimated 3,700 women die of cervical cancer. Around the world, it is nearer to 270,000.

According to the national Cancer Institute, Human Papillomaviruses (HPV’s) “are the major cause of cervical cancer.” In addition to this, they may cause other cancers.

HPVs are now recognized as the major cause of cervical cancer. Studies also suggest that HPVs may play a role in cancers of the anus, vulva, vagina and some cancers of the oropharynx (the middle part of the throat that includes the soft palate, the base of the tongue and the tonsils).

The National Cancer Institute also says that there is no cure for HPV infection – but that soon will not be true.

You see, they have come out with a vaccine to eliminate HPV. The tests are nearly complete, and we may see the HPV vaccine on the market soon.

From myDNA:
The human papillomavirus (HPV)vaccine, Cervarix, has passed another hurdle. The latest study shows the medication protects women against HPV strains that cause up to 70 percent of all cervical cancers for at least a four-year period. […]

Cervarix protects against four strains of HPV that cause nearly all cervical cancers. It was found to be 100 percent effective against HPV strains 16 and 18, nearly 100 percent effective agianst HPV 45, and 50 percent effective against HPV 31.

This vaccine can cut the number of cervical cancer deaths drastically. It can save thousands of lives in the United States and hundreds of thousands of lives around the world. Not only can it save lives, it can also save millions of dollars nationwide.

From the New Republic:
It’s also true that the annual number of cervical cancer cases is relatively small–10,400; a third of which are fatal. But each year, 4.7 million American women require one or more follow-up appointments for an abnormal pap result, and at least 3 million of these cases result from having HPV. The cost of these appointments to the indiviudual (and to our already overburdened health care system) quickly adds up. A 2003 Stanford study suggested that the cost of inoculating people against the disease would be far smaller than the current cost to the health care system associated with HPV.

It saves lives, it saves money…so what’s the problem?

Well, the Religious Right isn’t happy with the vaccine. The right-wing groups Family Research Council and Focus on the Family say they are happy with the vaccines agains HPV. But then they turn around and say they want people to have a choice to have the shot. They want a choice to take a vaccine that would save thousands of lives. And their position is that they don’t want people to take the shots.

Instead they prefer abstenence instead of an immunization. Would they prefer that people avoid activites that could cause tetanus instead of getting a booster shot? The idea is ludicrous. The expense in both dollars and in precious lives would outweigh everything else; the moral thing to do would be to save lives.

But they aren’t in the business of saving lives, apparently. They use their convoluted logic to say that once people get ther HPV shots, they are going to go out and have wild, promiscous ses, with the knowledge that they are safe from HPV (and so from cervical cancer).

For example:
Bridget Maher of the Family Reserach Council, a leading Christian lobby group based in Washington, D.C. told the British magazine New Scientist in APril 2005 that, “Giving the HPV vaccine to youn women could be potentially harmful, because they may see it as a license to engage in premarital sex.”

Yeah, in the same way that once people get ther tetanus shots, the immediately see it as a license to step on nails. After all, they are protected.

The Religious Right is clearly out of bounds on this issue; they have no moral standing. To not back widespread use of the HPV vaccine can only harm; the only outcome would be that people who don’t take the vaccine are more susceptible to cancer.

April, 2006|Archive|

Paltrow Family Honors Dad’s Memory by Advocating for Cancer Awareness

  • 4/27/2006
  • New York, NY
  • staff
  • ABC News Health (www.abcnews.go.com)

After Bruce Paltrow died in 2002, his wife, Blythe Danner, began fighting to raise awareness about head and neck cancer, which is diagnosed in 40,000 Americans every year and kills 11,000.

“It means a lot to get the word out,” Danner said. “It’s a very unrecognized cancer.”

Paltrow was first diagnosed with cancer in the fall of 1998. He had been hoarse for months but had refused to go to the doctor. By the time he went, the cancer was in stage IV.

“Because it was hidden way back in [his] throat, it was hard to detect,” Danner said. “Stage I or II, he’d still be with us, I think.”

Regular dental checkups are important to early detection, because dentists often see the first signs of the disease, like unusual white spots on the gums or jaws.

There are particular warning signs of head and neck cancer:

Persistent sore throat and hoarseness
Lingering pain in the mouth
An unhealed lump on the mouth or neck
Ear pain on one side only
Sinuses that don’t clear

Paltrow underwent six weeks of radiation therapy, and he went into remission for four years. Then, in October 2002, he flew to Italy for his daughter Gwyneth Paltrow’s 30th birthday. Friends discovered him in his room after the celebration throwing up blood. Gwyneth forced him to go to the hospital, where doctors discovered that his cancer had returned. He died before any other family member could fly to Italy.

Gwyneth talked about her grief with Diane Sawyer in 2003.

“The amazing thing is how unprepared we are in this culture for grief,” Gwyneth said. “And it is a monster. I mean, it is a monster. You know, there were some days where I thought, I can’t believe I’m waking up. I can’t believe I’m still alive. I mean, the weight of the pain was so great. But you just keep waking up.”

Danner said one of her husband’s favorite quotes was from poet Robert Frost: “In three words I can sum up everything I’ve learned about life. It goes on.”

“He would not want us to wallow,” Danner said. Instead, the actress is working to educate others.

“Early detection, prevention, it just has to be out there much more, and it hasn’t been out there in the mainstream media.”

Danner said she hoped to reduce the rate of head and neck cancer by the time her grandchildren from Gwyneth and Coldplay singer Chris Martin were grown.

“They [Moses and Apple] are what has given life a meaning again to me,” Danner said.

To learn more about head and neck cancer, visit www.speakouthnc.com

April, 2006|Archive|

18F-FDG PET/CT for Detecting Nodal Metastases in Patients with Oral Cancer Staged N0 by Clinical Examination and CT/MRI

  • 4/27/2006
  • New York, NY
  • Heiko Schöder et al.
  • Journal of Nuclear Medicine Vol. 47 No. 5 755-762

Introduction:
18F-FDG PET has a high accuracy in staging head and neck cancer, but its role in patients with clinically and radiographically negative necks (N0) is less clear. In particular, the value of combined PET/CT has not been determined in this group of patients.

Methods:
In a prospective study, 31 patients with oral cancer and no evidence of lymph node metastases by clinical examination or CT/MRI underwent 18F-FDG PET/CT before elective neck dissection. PET/CT findings were recorded by neck side (left or right) and lymph node level. PET/CT findings were compared with histopathology of dissected nodes, which was the standard of reference.

Results:
Elective neck dissections (26 unilateral, 5 bilateral; a total of 36 neck sides), involving 142 nodal levels, were performed. Only 13 of 765 dissected lymph nodes harbored metastases. Histopathology revealed nodal metastases in 9 of 36 neck sides and 9 of 142 nodal levels.
PET was TP in 6 nodal levels (6 neck sides), false-negative in 3 levels (3 neck sides), true-negative in 127 levels (23 neck sides), and false-positive in 6 levels (4 neck sides).
The 3 false-negative findings occurred in metastases smaller than 3 mm or because of inability to distinguish between primary tumor and adjacent metastasis. TP and false-positive nodes exhibited similar standardized uptakes (4.8 ± 1.1 vs. 4.2 ± 1.0; P = not significant). Sensitivity and specificity were 67% and 85% on the basis of neck sides and 67% and 95% on the basis of number of nodal levels, respectively.
If a decision regarding the need for neck dissection had been based solely on PET/CT, 3 false-negative necks would have been undertreated, and 4 false-positive necks would have been overtreated.

Conclusion:
18F-FDG PET/CT can identify lymph node metastases in a segment of patients with oral cancer and N0 neck. A negative test can exclude metastatic deposits with high specificity. Despite reasonably high overall accuracy, however, the clinical application of PET/CT in the N0 neck may be limited by the combination of limited sensitivity for small metastatic deposits and a relatively high number of false-positive findings. The surgical management of the N0 neck should therefore not be based on PET/CT findings alone.

Authors:
Heiko Schöder1, Diane L. Carlson2, Dennis H. Kraus3, Hilda E. Stambuk1, Mithat Gönen4, Yusuf E. Erdi5, Henry W.D. Yeung1, Andrew G. Huvos2, Jatin P. Shah3, Steven M. Larson1 and Richard J. Wong3

Authors’ affiliation:
1 Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York;
2 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York;
3 Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York;
4 Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, New York; and
5 Department of Physics, Memorial Sloan-Kettering Cancer Center, New York, New York

April, 2006|Archive|

Cancer advice: Eat your berries

  • 4/27/2006
  • Louisville, KY
  • Laura Ungar
  • The Courier-Journal (courier-journal.com)

University of Louisville researcher leads campaign

An apple a day may be a good thing, but a University of Louisville researcher argues that berries could be the real key to staving off cancer.

Ramesh Gupta is leading a research effort that has shown certain berries may help protect against two of the nation’s most deadly cancers: breast cancer and lung cancer.

“We’ve been told we need to eat more fruits and vegetables,” said Gupta, who is based at the James Graham Brown Cancer Center. “But berries certainly seem to come to the top of the list. ”

Gupta, who presented his breast-cancer findings to the American Association of Cancer Researchers in Washington, D.C., this month, found that eating antioxidant-rich blueberries and black raspberries reduced the size of breast tumors by 60 percent to 70 percent among rats exposed to estrogen.

His lung-cancer research, given at an earlier meeting of the association, showed that a mixture of four berries — strawberries, blueberries, black raspberries and blackberries — reduced the incidence and number of lung tumors by 30 percent to 35 percent in mice exposed to cigarette smoke. He is planning human tests in the next two years.

The research provides hope to people such as 71-year-old Harvey Plaschke of Louisville, whose wife, Amparo, died of lung cancer three years ago, at age 68. A nonsmoker, she had suffered pneumonia twice since 2000, then developed a persistent cough. She died shortly before their 40th anniversary.

“There needs to be a whole lot more research. Anything that’s being done is wonderful,” Plaschke said, adding that it’s especially relevant in Kentucky, which has the nation’s highest lung-cancer death rate.

Gupta’s findings are part of a growing body of berry-based research that gives credence to the idea that nature may provide answers to some of the most complex medical problems.

Last year researchers from the University of Kentucky and Ohio State University announced they would start testing a gel made of freeze-dried black raspberries for the prevention of oral cancer.

Other research has shown that black raspberries may prevent cancers of the gastrointestinal tract.

And James Joseph, a U.S. Department of Agriculture researcher based at Tufts University in Boston, has published findings about the protective qualities of berries against age-related neurodegenerative diseases such as Alzheimer’s.

One advantage of berries, researchers said, is that they don’t produce side effects. So Gupta doesn’t hesitate to put his research into practice, eating lots of berries and running frozen ones through a juicer to make a dessert he calls “berry smoosh.”

“Can you OD on them? No,” Joseph said. “That’s the beauty of berries. You can’t hurt yourself with them.”

Berries’ compounds key

Researchers say various types of berries contain different concentrations of antioxidant compounds — and diets rich in antioxidants can protect against harmful molecules called free radicals, which people are less able to fight off as they age.

“The compounds in the berries can turn on signals that are beneficial and turn off signals that are deleterious,” Joseph said.

Gupta said he’s not sure exactly which compounds, or combinations of compounds, are responsible for the results he’s seen.

In the breast-cancer research, his team exposed rats to natural estrogen, then fed some a regular diet and gave others blueberries, black raspberries or ellagic acid in doses equivalent to about a pound of fresh berries a day in humans. Ellagic acid is one of the compounds found in the berries.

After six months, tumor incidence was the same among the groups. But black raspberries and ellagic acid each reduced the number of tumors by 40 percent to 50 percent and tumor size by 60 percent to 70 percent. Blueberries reduced the size of tumors by 50 percent but didn’t affect the number of tumors.

Gupta — whose team receives federal but no commercial funding — said his is the first report on the effectiveness of berries against estrogen-related breast cancer. Joseph agreed he had not heard of others doing the same research.

For the lung-cancer experiments, Gupta’s team exposed a particular type of cancer-prone mice to cigarette smoke for five months. They then compared those fed a regular diet and those given a mixture of strawberries, blueberries, black raspberries and blackberries.

Gupta is working with Dr. Goetz Kloecker, director of the Thoracic Oncology Clinic at the Brown Cancer Center, to develop a plan for human lung-cancer trials.

Targeting oral cancer

The University of Kentucky’s berry research addresses another tobacco-related cancer that hits Kentucky hard: oral cancer.

The black raspberry gel was developed by researchers at UK’s Center for Pharmaceutical Science, working with Ohio researchers.

Under their study, which involves 20 patients with oral lesions, surgeons remove part of the lesions to analyze them, and the patients then apply the gel four times a day for six weeks. Then, the rest of the lesion is removed, and researchers study whether the berries have helped.

Gupta said it should not be surprising that berries are proving so beneficial — they’ve been considered a folk medicine for thousands of years in many cultures. The modern world is just finally catching up, he said. “The message is getting out.”

April, 2006|Archive|

Cytokinetics Announces Clinical Trials Data to be Presented at the 2006 Annual Meeting of The American Society of Clinical Oncology

  • 4/25/2006
  • San Francisco, CA
  • press release
  • prnewsire.com

Cytokinetics, Incorporated announced today that five abstracts summarizing data from clinical trials conducted by GlaxoSmithKline (GSK) or the National Cancer Institute (NCI) evaluating ispinesib (SB-715992) or SB- 743921 will be presented at the 2006 Annual Meeting of the American Society of Clinical Oncology (ASCO) in Atlanta, Georgia.

Ispinesib and SB-743921 are both novel, chemically distinct, small molecule inhibitors of kinesin spindle protein (KSP), a mitotic kinesin essential for proper cell division. Both drug candidates have arisen from a broad strategic collaboration between Cytokinetics and GSK to discover, develop and commercialize novel small molecule therapeutics targeting human mitotic kinesins for applications in the treatment of cancer and other diseases.

Abstract:
A Phase II Study of SB-715992 (Ispinesib) in Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma (RMHNSC). Abstract will be published in the ASCO 2006 Annual Meeting Proceedings.

About Ispinesib
Ispinesib is a novel small molecule inhibitor of Kinesin Spindle Protein (KSP), a mitotic kinesin protein essential for proper cell division. Ispinesib is the first drug candidate in clinical development that has arisen from a broad strategic collaboration between Cytokinetics and GSK to discover, develop and commercialize novel small molecule therapeutics targeting human mitotic kinesins for applications in the treatment of cancer and other diseases. GSK is conducting a broad clinical trials program for ispinesib designed to study this drug candidate in multiple tumor types, combination regimens and dosing schedules.

GSK is currently evaluating ispinesib in two Phase II clinical trials being conducted in patients with each of ovarian and breast cancers and two Phase Ib clinical trials designed to evaluate ispinesib in combination with each of carboplatin and capecitabine. Interim data from the ongoing breast cancer clinical trial and data from the platinum-refractory and the platinum-sensitive treatment arms of the non-small cell lung cancer clinical trial were announced recently.

In the Phase II clinical trial enrolling patients with advanced breast cancer, the best overall responses observed with ispinesib administered as monotherapy have been partial responses in 3 of 33 evaluable patients to date. These 3 patients had maximum decrease in tumor size ranging from 46% to 68% with the duration of response ranging from 7.1 weeks to 13.4 weeks. The overall response rate in this clinical trial for all 33 evaluable patients was 9% with an overall median time to progression of 5.7 weeks.

In the platinum-refractory treatment arm of a Phase II clinical trial enrolling patients with non-small cell lung cancer, the best overall response observed with ispinesib administered as monotherapy was disease stabilization in 25% of evaluable patients (N=20) with a median time to progression (TTP) of 12 weeks (overall median TTP was 6 weeks). In the platinum-sensitive treatment arm of this Phase II clinical trial, the best overall response observed with ispinesib administered as monotherapy was disease stabilization in 50% of evaluable patients (N=20) with a median TTP of 17 weeks (overall median TTP was 6 weeks).

For both clinical trials, the adverse events were manageable, predictable, and consistent with the Phase I experience. The most common adverse event was Grade 4 neutropenia. In addition to the ongoing studies being conducted by GSK, the National Cancer Institute (NCI) is sponsoring five other Phase II clinical trials evaluating ispinesib in other tumor types, including melanoma, head and neck, hepatocellular, colorectal and prostate cancers. In addition, the NCI plans to conduct an additional Phase II clinical trial in patients with renal cell carcinoma. The NCI is also conducting two other Phase I clinical trials evaluating an alternative schedule of ispinesib in leukemia and advanced solid tum

April, 2006|Archive|

Prospective study of alcohol consumption and risk of oral premalignant lesions in men

  • 4/24/2006
  • Watertown, MA
  • NN Maser et al.
  • Cancer Epidemiol. Biomarkers Prev., April 1, 2006; 15(4): 774-81

Recent case-control studies indicate that alcohol increases the risk of oral premalignant lesions (OPL) among tobacco users, but the independent association between alcohol and OPL remains unclear. We prospectively evaluated the association between alcohol consumption and the incidence of OPL.

Participants were 41,458 men in the Health Professionals Follow-up Study. Alcohol consumption was assessed every 4 years using validated food frequency questionnaires. We confirmed clinically or histopathologically diagnosed OPL events occurring between 1986 and 2002 by medical record review (193 cases). Multivariate-adjusted relative risks of OPL were calculated from Cox proportional hazards models.

With detailed control for tobacco and other variables, multivariate relative risks (95% confidence intervals) were 1.7 (0.9-3.2) for drinkers of 0.1 to 14.9 g/d, 2.9 (1.5-5.6) for 15 to 29.9 g/d, and 2.5 (1.3-5.1) for >/=30 g/d, compared with nondrinkers.

Approximately one additional drink per day (12.5 g) was associated with a 22% increase in risk (P < 0.001). The associations did not vary by beverage type, frequency, or consumption with meals.

Results were similar when restricted to cases of oral epithelial dysplasia. Alcohol increased OPL risk in never-users of tobacco as well as in past or current users. An interaction between alcohol and tobacco was apparent by their more-than-additive joint effects.

Alcohol is an independent risk factor for OPL, regardless of beverage type or drinking pattern. Recommendations to reduce alcohol intake have the potential to reduce incidence of OPL in nonsmokers and smokers alike.

Authors:
NN Maserejian, KJ Joshipura, BA Rosner, E Giovannucci, and AI Zavras

Authors’ affiliation:
New England Research Institutes, 9 Galen Street, Watertown, MA 02472

April, 2006|Archive|

Possible cause and potential treatment found for aggressive head and neck cancer

  • 4/22/2006
  • San Francisco, CA
  • press release
  • EurekAlert (www.eurekalert.com

Researchers at the San Francisco VA Medical Center report that they have found a potential molecular cause for the aggressive growth and spread of human head and neck squamous cell carcinoma, a highly malignant form of cancer with a very high death rate.
The discovery could potentially lead to new treatments as well, say the researchers.

Their key finding is the triple interaction between three players: CD44, a surface receptor molecule that plays an important role in a variety of cellular functions; hyaluronan (HA), a complex carbohydrate found in the connective tissues between cells; and LARG, a signal activator found in tumor cells.

That interaction apparently initiates two molecular pathways that simultaneously cause tumor cell growth and tumor cell migration, says lead author Lilly Bourguignon, PhD, a research career scientist at SFVAMC and a professor of medicine at the University of California, San Francisco.

The study results are reported in the current on-line “In Press” section of the Journal of Biological Chemistry.

Working with human cancer cells in culture, Bourguignon and her team found that HA mediates the interaction between CD44 and LARG in a way that stimulates a molecular pathway called RhoA. Through a series of complex steps, the RhoA pathway causes the tumor cell’s cytoskeleton – the structure that maintains the cell’s shape – to reorganize in a way that causes tumor cells to migrate to other sites in the body, resulting in cancer metastasis.

At the same time, the HA-mediated CD44/LARG complex also binds with epidermal growth factor receptor (EGFR), located on the tumor cell’s surface, which sets off a second molecular pathway called Ras. In turn, the Ras pathway promotes tumor cell growth.

The result, according to Bourguignon, is an aggressive, fast-growing, and invasive cancer. “The combination of RhoA and Ras pathway activation is deadly,” she says.

Bourguignon cautions that “this is not the only mechanism” by which aggressive head and neck squamous cell carcinoma grows and spreads, “but it is an important mechanism.”

Because LARG is a central player in these molecular interactions, says Bourguignon, it may be the key to a potential treatment that could prevent both pathways from being initiated in the first place.

She and her fellow researchers found that when a particular segment of LARG, called the PDZ domain, is introduced to the tumor cell, it binds up all available CD44 and EGFR, leaving them unavailable to initiate the deadly twin molecular pathways.

“We have used the molecular binding action of LARG-PDZ against itself,” says Bourguignon. “In the future, LARG could be utilized as a drug target leading to a new therapeutic strategy.”

Currently, there are no really effective chemotherapeutic treatments for human head and neck squamous cell carcinoma, according to Bourguignon. “There are drugs that block EGFR action, but they are not entirely effective,” she notes.

Bourguignon says that since the presence of EGFR marks particularly aggressive cancers, “the CD44/EGFR complex can be used as a marker for potentially aggressive head-neck tumors. This could be correlated with tumor degree and tumor progression in each patient to get a much more accurate picture of the cancer. Most importantly, this complex may be used a clinical predictor for evaluating the potential of head and neck cancers to metastasize,” or spread beyond the initial tumor site.

Co-authors of the study are Eli Gilad, PhD, Amy Brightman, BS, Falko Diedrich, MD, and Patrick Singleton, PhD, all of SFVAMC.

The research was funded by grants from the United States Public Health Service that were administered by the Northern California Institute for Research and Education, and a grant from the Department of Veterans Affairs.

April, 2006|Archive|