Ovarian Cancer Research

Last Update: March 2007

Vitamin C Infusion Therapy

University of Kansas Medical Center physician Jeanne Drisko received $375,000 for a trial of 30 ovarian cancer patients. In Montreal, McGill University oncologist Wilson Miller received $300,000 to find the maximum safe doses for treating various cancers. Both studies feature the intravenous use of high levels of vitamin C as a cancer treatment.

The Kansas study began in 2002 and enrolled patients until 2005. Women with ovarian cancer were given doses of vitamin C intravenously twice a week while also undergoing conventional chemotherapy treatment.

When vitamin C — also called ascorbate — is administered by vein in high doses, it generates hydrogen peroxide in the cellular areas, Drisko said. “The machinery of a cancer cell is different,” Drisko said. “That machinery is particularly susceptible to being knocked off by hydrogen peroxide. … What’s exciting about this is that normal cells are completely unharmed.... We haven’t had any adverse events,” she said. “We’re encouraged enough that we’re continuing.”

Vitamin C is known to have effects on immune function, and it is believed that the body requires more vitamin C during physical or chemical stress. Epidemiological studies showed reduced risk of some cancers in populations with high vitamin C intake. This may be due to vitamin C's antioxidant effect or its ability to block N-nitrosamines formed in the stomach after ingestion of certain foods. There is a close association between high vitamin C levels and reduced risk of stomach cancer. In animal studies, tumor regression, tumor growth inhibition, and increased survival have been noted. However, two randomized studies in patients with advanced cancer had negative results.

Mega dose vitamin C can cause stomach irritation, headache, rash, and increased oxalate deposition in bladder/kidneys. Vitamin C can interfere with medications including anticoagulants, iron, vitamin B12, and vitamin E. High doses in pregnancy can lead to vitamin C deficiency in the newborn.

There is considerable difference between Vitamin C taken orally, and vitamin C taken intravenously The vitamin C trials that failed in the past were oral. Recent "success" suggest that intravenous administration has positive effects.

Dr. Mark Levine and his colleagues at the National Institutes of Health have published insightful pharmacological studies on vitamin C showing how much of orally ingested and intravenous doses gets into the blood and how quickly it is excreted. According to these studies, the plasma concentration achieved with intravenous vitamin C is over 25 times higher than oral vitamin C and could reach 70-fold higher concentrations. These very high concentrations are similar to those that have been reported to kill cancer cells in culture. In addition to the results reported by Pauling and his two medical collaborators, Cameron and Dr. Abram Hoffer, anecdotal clinical evidence supports the selective cytotoxicity of vitamin C for cancer cells, including a report from the University of Kansas on the beneficial effect of intravenous vitamin C in two women with stage III ovarian carcinoma.

A new paper by Levine’s group published in the September 20th issue of the Proceedings of the National Academy of Sciences USA offers more evidence that pharmacological concentrations of vitamin C preferentially kill cancer cells. Ten human cancer cell lines and four normal cell types were studied. Vitamin C at concentrations easily achieved by intravenous administration effectively killed cancer cells by apoptosis (programmed cell death) and necrosis, but did not harm normal cells.

Vitamin K-3 and Vitamin C : In a 1/100 combination these vitamins cause ovarian cancer cells to self destruct. Studies with other cancer types, suggest this vitamin combination may make cancer cells more sensitive to chemotherapy treatment.

NCI Issues Clinical Announcement for Preferred Method of Treatment for Advanced Ovarian Cancer

The National Cancer Institute (NCI), part of the National Institutes of Health, announced encouraging new treatment strategies for women with advanced ovarian cancer. The combined methods, which deliver drugs into a vein and directly into the abdomen, extend overall survival for women with advanced ovarian cancer by about a year.

The clinical announcement to surgeons and other medical professionals who treat women with ovarian cancer was made with the support of six professional societies and advocacy groups. The announcement coincides with publication in the New England Journal of Medicine* of the results of a large clinical trial by Deborah Armstrong, M.D., medical oncologist and an associate professor at Johns Hopkins Kimmel Cancer Center in Baltimore, Md., and her colleagues in an NCI-supported research network known as the Gynecologic Oncology Group (GOG). This is the eighth trial evaluating the use of chemotherapy delivered into the abdomen for ovarian cancer. Together, these trials show a significant improvement in survival for women with advanced ovarian cancer.

The two treatment methods are called intravenous, or IV, for chemotherapy delivered into a vein and intraperitoneal, or IP, for chemotherapy delivered into the abdominal, or peritoneal, cavity. The Armstrong trial involved 429 women with stage III ovarian cancer who were given chemotherapy following the successful surgical removal of tumors. It compared two treatment regimens: 1) IV paclitaxel followed by IV cisplatin, to 2) IV paclitaxel followed by IP cisplatin and the subsequent administration of IP paclitaxel.

"IP therapy is not a new treatment approach, but it has not been widely accepted as the gold standard for women with ovarian cancer," said Armstrong. "There has been a prejudice against IP therapy in ovarian cancer because it's an old idea, it requires skill and experience for the surgery and for the chemotherapy, and it's more complicated than IV chemotherapy. But now we have firm data showing that we should use a combination of IP and IV chemotherapy in most women with advanced ovarian cancer who have had successful surgery to remove the bulk of their tumor."

Standard treatment for women with stage III ovarian cancer has been surgical removal of the tumor (debulking), followed by six to eight courses of IV chemotherapy given every three weeks with a platinum drug, such as cisplatin or carboplatin, and a taxane drug, such as paclitaxel. The new NCI clinical announcement recommends that women with advanced ovarian cancer who undergo effective surgical debulking receive a combination of IV and IP chemotherapy. IP chemotherapy allows higher doses and more frequent administration of drugs, and it appears to be more effective in killing cancer cells in the peritoneal cavity, where ovarian cancer is likely to spread or recur first.

More studies are needed to determine the best IP drug regimen and the optimal number of IP treatments. Future trials also will address how to reduce toxicity associated with IP administration.

Personal Profiling Ovarian Cancer

Is it possible to get a personal profile for your specific variety of ovarian cancer? Can companies determine genetic variables from the cancer tissue taken from your body? Can these tests determine if your cancer is aggressive or less so? The answers to these important questions are getting nearer as the molecular/genetic revolution moves rapidly forward. My answer, for the moment is "I don't have a clue." Here is Anne Helman's comments:

"There is a terrific company called Phenopath Laborotories that does reliable and accurate tissue testing on both new and parrafin stored tissue samples. They have a comprehensive list of antibody (and other specialized) tests. If an oncologist orders a test, insurance will usually pay.

"There are various companies who perform testing. Phenopath tests for protein expressions and antibodies. You can go onto their site and look at the list of tests they do. If, while on the page of tests, you do a word search for "ovary" or "ovarian", the function will highlight, one at a time, each test they do that may have something to do with ovarian cancer. Of course, there are other things that won't highlight, such as CD25 protein expression - just as an example, that is something that is being looked at by researchers studying TREGS immunotherapy treatments. Some believe that over-expression of this protein may signal a better response to a drug like Ontak. If you test for COX-2 expression you may find that there is or is not over-expression. If there is, then a drug like Celebrex may be added to the protocol to try to squelch the inflammation pathway. We know from research that COX-2 (and COX-1) are implicated in the proliferation of ovarian cancer (and other cancers). But, if the COX-2 test is negative, no need to take Celebrex.

"There are other tests, the erb-B1 panel which tests for Estrogen and Progesterone Receptors to see whether they are positive or negative. This is something your hospital should be able to do for you, it's immunohistochemistry staining. If you do it, ask them to quantify if the ER is positive, so you know what percentage. If highly ER positive, then an endocrine therapy may be useful at some point in time. Endocrine therapies may be Tamoxifen, Tamoxifen and Megace together, Arimidex. There is research on ovarian and Tamoxifen. I don't personally care for the drug Megace due to it's side effects. This same panel test includes a test for HER2/neu - - if that is over-expressed (not common in ovarian, but does happen), the drug Herceptin is the antidote. You may have heard about it in the news vis-a-vis breast cancer since it's much more commonly over-expressed in breast cancer. But I know women who take Herceptin and it keeps the cancer at bay.

"You can also test for EGF and VEGF - - these are the growth pathways.

"Additional testing can be done for chemo resistency or sensitivity, but can't be done when one is on chemo. Must be off chemo for at least one month before grabbing new tissue to send. There are 3 labs who do this: Oncotech; Rational Therapeutics and Weisenthal Cancer Group. You can find them all on the web. They do slightly different things. I used Weisenthal and had ascites sent out so the cells in the ascites could be cultured and tested. This is not a perfect science because what happens in a dish may or may not carry over to what happens in the body with the same drugs. Usually, though, if resistant in the dish, one is resistant in the body. Oncotech has contracts with most major hospitals to have tumor tissue tested and is covered by insurance. The other two are not covered by insurance, although I did get my insurance to pay for a small portion because Dr. Weisenthal billed some of the fee as a consult. Dr. Nagourney is with Rational Therapeutics; he and Weisenthal used to work together (I think they started Oncotech). If I were to assay again, am not sure whether I would use Rational or Oncotech."

Gene linked to Ovarian Cancer

Research by Tian-Li Wang and her colleagues at John Hopkins University School of Medicine suggest that over-production of a gene called Rsf-1 may play a role in the development of ovarian cancer. Over-production of Rsf-1 on chromosome 11 caused aggressive ovarian cancer; the more times the gene was expressed (replicated on chromosome 11) the more aggressive the cancer and the more dangerous the outcome. This finding could lead to drugs that block Rsf-1 activity.

Dendrimers and Ovarian Cancer

Dr. James Baker, director of the Center for Biologic Nanotechnology.at the University of Michigan has a grant from the National Cancer Institute's Unconventional Innovations Program. Researchers at the Center are working on "smart" drug delivery devices that will knock out cancer cells with lethal doses, leaving normal cells unharmed, and even reporting back on their success. The U-M group is using lab-made molecules called dendrimers, also known as nanoparticles, as the backbones of their delivery system. Dendrimers are tiny spheres whose width is ten thousand times smaller than the thickness of a human hair. These spheres have all sorts of loose ends where you can attach things—for example, a targeting agent that can recognize a cancer cell and distinguish it from a healthy cell. You can also attach the drug that actually kills the cancer cells. If you have both of these functions on the same molecule, then you have a smart drug that knows which cells to attack." Early results of studies with mice show that the nanoparticle drugs do treat cancer effectively with fewer side effects than conventional chemotherapy drugs, just as the researchers had hoped. So far, the technique has been shown to work only on head and neck squamous cancer in mice; but similar cancers, such as bladder and ovarian cancer, might also respond.

Nanotechnology and Ovarian Cancer

The National Cancer Institute (NCI), part of the National Institutes of Health (NIH), announced (October, 2005) funding for a major component of its $144.3 million, five-year initiative for nanotechnology in cancer research. Awards totaling $35 million over five years, with $7 million total in the first year, will establish 12 Cancer Nanotechnology Platform Partnerships.

"The future of oncology - and the opportunity to eliminate the suffering and death due to cancer - will hinge upon our ability to confront cancer at its molecular level," said Andrew von Eschenbach, M.D., director of the National Cancer Institute. "Nanodevices, invisible to the naked eye and a tiny fraction the width of a human hair, will enable researchers to probe genetic defects inside cells, detect the earliest aberrations of cellular function that lead to cancer, and correct those errant processes long before they give rise to cancers large enough to be diagnosed by today's methods."

Nanotechnology, the development and engineering of devices so small that they are measured on a molecular scale, already has demonstrated promising results in cancer research and treatment. In September 2004, the NCI launched the NCI Alliance for Nanotechnology in Cancer as a comprehensive, integrated initiative to develop and translate cancer-related nanotechnology research into clinical practice.

The NCI Alliance for Nanotechnology in Cancer encompasses four major program components, including the Cancer Nanotechnology Platform Partnerships. These partnerships, modeled after the NIH Bioengineering Research Partnerships, are designed to develop technologies for new products in six key programmatic areas: molecular imaging and early detection, in vivo imaging, reporters of efficacy (e.g., real-time assessments of treatment), multifunctional therapeutics, prevention and control, and research enablers (opening new pathways for research).

The awards reflect a cross-section of technologies, disciplines, cancer types, geographies, and risk/reward profiles, and will link universities to NCI-Designated Cancer Centers. One of the major awards went to ovarian cancer researchers: Photo destruction of Ovarian Cancer: ErbB3 Targeted Aptamer-Nanoparticle Conjugate, Massachusetts General Hospital, Boston, Mass. Principal investigator: Tayyaba Hasan, Ph.D. The goal is selective killing of targeted ovarian cancer cells while leaving normal tissue unaffected.

Photo dynamic therapy (PDT) is a process in which a light-responsive chemical, when exposed to the appropriate wavelength of light, is activated to undergo either a photo physical process or to initiate photochemistry, producing molecular species which can interact with biological targets (photosensitization). Such interactions can be exploited for biomedical applications or for basic studies. Photosensitization is exploited for the destruction of tumors and certain non-neoplastic target tissues in an approach termed Photo dynamic therapy (PDT). Compounds, typically porphyrins, are localized in target cells and tissues and upon light activation cause destruction at sites of localization. An advantage of this approach is that it minimizes normal tissue damage.


Differences in Ovarian Cancer Cells and Normal Ovarian Cells

Comparison of normal ovarian cells with advanced ovarian cancer cells demonstrated genetic differences (study at the Medical University of Vienna, Clinic for Internal Medicine). In normal ovarian cells two genes are always activated, N33 and EFA6R. In some cases, these genes are almost completely inactivated in ovarian cancer cells. It appears as if these genes lose their ability to function before the onset of clinical symptoms, and are therefore good candidates for early identification of the disease.


Kurume University School of Medicine Topoisomerase Comparative Study

S. Nishio, T. Sugiyama, T. Shouji, A. Yoshizaki, R. Kitagawa, K. Ushijima, T. Kamura

Kurume University School of Medicine, Obstetrics and Gynecology, Kurume, Japan
Iwate Medical University School of Medicine, Obstetrics and Gynecology, Morioka, Japan

Purpose: To evaluate the efficacy and toxicity of intravenous irinotecan (topoisomerase-I inhibitor) and oral etoposide (topoisomerase-II inhibitor) as combination chemotherapy in patients with platinum/taxane-refractory or -resistant ovarian carcinoma.

Patients and methods: Between October 2002 and September 2004, 28 patients with platinum- and taxane-refractory or resistant ovarian carcinoma were enrolled in this study. The eligible patients had received at least one prior chemotherapy including both platinum and taxane. Irinotecan 70 mg/m2 was administered intravenously for 90 minutes infusion on days 1 and 15, and etoposide 50 mg/body orally on days 1 to 21 in principle. In consideration of safety of this study, the initial doses were set to CPT-11 60 mg/m2 and etoposide 50 mg/body for heavy pretreated patients. The treatment courses were repeated every 4 weeks. Subsequent doses were unchanged, reduced, or omitted according to the observed toxicity and protocol guidelines. Patients were evaluated for response using the RECIST or CA-125 criteria and for toxicity using NCI-CTC Version 3.

Results: All of 28 patients were eligible and assessable. There were 10 partial responses (PRs) and one complete response (CR) for an overall response rate of 39.3% (95% confidence interval, 23.6% to 57.6%). The progression-free rate (CR/PR+stable disease rate) was 82.1%. The overall median response and stable disease duration was 7.0+ months and 8.0+ months, respectively. The major toxicity was neutropenia, with 21.4% grade 3 and 39.3% grade 4 reported. Diarrhea was infrequent and mild, and gastrointestinal toxicity was moderate and manageable. Febrile neutropenia of grade 3 or higher occurred in four cases (14.3%). They were improved by the administration of antibiotics. There were no treatment-related deaths.

Conclusions: Irinotecan/oral etoposide showed a favorable response rate to platinum/taxane-resistant ovarian cancer. Furthermore, the progression-free rate exceeded 80% if stable disease was included. It had no increased hematological toxicity when compared to irinotecan single-agent. Or rather, diarrhea was more mitigated than by an irinotecan single-agent. It was shown that irinotecan/oral etoposide was a promising combination therapy as a salvage therapy from the viewpoint of effect and toxicity.


A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumors

Penson RT, Seiden MV, Matulonis UA, Appleman LJ, Fuller AF, Goodman A, Campos SM, Clark JW, Roche M, Eder JP.

Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. rpenson@partners.org

The goal of this phase I study was to develop a novel schedule using oral etoposide and infusional topotecan as a continually alternating schedule with potentially optimal reciprocal induction of the non target topoisomerase. The initial etoposide dose was 15 mg m(-2) b.i.d. days (D)1-5 weeks 1,3,5,7,9 and 11, escalated 5 mg per dose per dose level (DL). Topotecan in weeks 2,4,6,8,10 and 12 was administered by 96 h infusion at an initial dose of 0.2 mg m(-2) day(-1) with a dose escalation of 0.1, then at 0.05 mg m(-2) day(-1). Eligibility criteria required no organ dysfunction. Two dose reductions or delays were allowed. A total of 36 patients with a median age of 57 (22-78) years, received a median 8 (2-19) weeks of chemotherapy. At DL 6, dose-limiting toxicities consisted of grade 3 nausea, vomiting and intolerable fatigue. Three patients developed a line-related thrombosis or infection and one subsequently developed AML. There was no febrile neutropenia.

There were six radiologically confirmed responses (18%) and 56% of patients demonstrated a response or stable disease, typically with only modest toxicity. Oral etoposide 35 mg m(-2) b.i.d. D1-5 and 1.8 mg m(-2) 96 h (total dose) infusional topotecan D8-11 can be administered on an alternating continual weekly schedule for at least 12 weeks, with promising clinical activity.


Novel Immunotherapeutic Approaches for Ovarian Cancer

Principal Investigator(s): Donald Kufe, M.D., David Avigan, M.D.

We developed a vaccine for patients with cancer by fusing their tumor cells with dendritic cells (DC). Fusion cell vaccines have been shown to be effective in the treatment of metastatic mouse tumor models and in reversing immunologic unresponsiveness to the human MUC1 carcinoma antigen in MUC1-transgenic mice. A Phase I clinical trial of the fusion cell vaccine demonstrated the induction of immunologic and clinical responses. Our overall hypothesis is that ovarian cancer cells express antigens that can be exploited as targets for the induction of anti-tumor immunity. Certain ovarian carcinoma-associated antigens, such as the MUC1 glycoprotein, represent known targets. Given the genetic instability associated with progression of human tumors, there are conceivably many epitopes unique to ovarian cancer cells that, while unknown, represent additional targets for vaccine therapy.

Our objective is to develop a fusion cell vaccine that induces immunity against multiple antigens expressed by ovarian cancer cells, is associated with substantial clinical efficacy and is non-toxic. Our hypotheses are that we can generate an effective fusion cell vaccine for the treatment of ovarian cancer by:

1) using mature autologous DC;

2) combining the vaccine with recombinant human IL-12 (rhIL-12); and

3) vaccinating patients with metastatic disease earlier in their treatment course.

Effectiveness of the fusion cell vaccine will be assessed in vitro and in a Phase I/II trial that monitors anti-tumor activity and induction of immunity in patients with advanced ovarian cancer. The findings from these studies will be used to design a Phase II study to compare the efficacy of the approach and a vaccinia virus-based vaccine that targets the MUC1 antigen (rV-MUC1+rV-TRICOM). The development of vaccines that are non-toxic and effective against advanced ovarian cancer could provide alternative treatment options and potentially improve prognosis for patients with this disease. The specific aims are:

1) To assess fusions of ovarian carcinoma cells with immature and mature autologous DC by evaluating cytokine production (IL-12, IL-10) and potency of the fusions in generating tumor specific immunity in vitro;

2) To conduct a Phase I/II trial of the ovarian carcinoma-DC fusion vaccine generated with mature DC and administered with rhIL-12;

3) To assess the induction of immunity against ovarian cancer cells and MUC1 in patients treated with the fusion cell vaccine alone and with rhIL-12; and

4) To perform a Phase II trial that will define the immunologic efficacy of the fusion cell vaccine and the rV-MUC1+rV-TRICOM vaccine in the treatment of patients with advanced ovarian cancer who have achieved a complete remission following primary chemotherapy.


Radiation Therapy May Be of Benefit in Women with Recurrent Ovarian Cancer

Researchers from Loyola University have reported that involved field radiation therapy is effective in controlling local recurrences of ovarian cancer, especially after optimal debulking surgery. The details of this phase II study appeared in the March 2005 issue of Gynecologic Oncology .

The majority of women with stage III and IV ovarian cancer are not cured with current combination chemotherapy regimens. Following recurrence, patients are usually treated with second-line combination chemotherapy regimens. The role of radiation therapy in palliating recurrent ovarian cancer has been more controversial, although this is considered a radiosensitive tumor.

In this recent study, 35 patients diagnosed with recurrent epithelial ovarian cancer received radiation therapy between 1991 and 2001. Twenty of the 35 patients received tumor-volume directed IFRT for localized disease recurrence either as a method of consolidating the disease after surgery or as an attempt to eliminate as much disease as possible when surgery was not an option. All patients had been heavily pretreated with multiple chemotherapy regimens. Eleven patients had successfully undergone surgery prior to radiation. The average radiation dose was 50.4Gy and IFRT was primarily completed with external beam radiation. Results of the study found that 17 of the 20 patients who received IFRT had a complete response following radiation. Analysis of local relapse-free survival, overall survival and disease-free survival at 5 years from the date of radiation was 66%, 34% and 34%, respectively. Local relapse-free survival at 3 years was 89% among those that had undergone successful surgery, compared to 42% for the patients who had residual disease after surgery or who were not considered eligible for surgery. At 3 years, disease-free survival was 72% among the surgical patients, compared to 22% among the patients who had not had surgery and the overall survival was 50% vs. 19%. Complications of radiation were mild, with approximately half of patients experiencing gastrointestinal symptoms.

Comments: It was concluded that involved field radiation therapy was an effective and well-tolerated treatment for controlling localized recurrences of ovarian cancer. These findings were particularly significant among patients who had completed surgery to eliminate as much cancer as possible. However, it was not clear whether this relatively small subset was representative of most women with recurrent ovarian cancer. Nevertheless, this study confirms that radiation can be a useful treatment for ovarian cancer.

Reference: Albuquerque K, Singla R, Potkul R. et al. Impact of Tumor Volume-Directed Involved Field Radiation Therapy Integrated in the Management of Recurrent Ovarian Cancer. Gynecologic Oncology. 2005; 96: 701-704.


Antidepressants do not promote ovarian cancer

(06 Apr 2005): Researchers have found no evidence to support a proposed link between antidepressant use and an increased risk of developing ovarian cancer.

Mechanisms by which antidepressants have been suggested to affect cancer growth have included that they could act as tumor promoters, that they increase the risk for cancer by suppressing immune function, and, more specifically to ovarian cancer, that their effect on levels of neurotransmitters such as serotonin or norepinephrine lead to increased gonadotropin secretion.

However, Patricia Moorman from Duke University Medical Center in Durham, North Carolina, USA, and colleagues found no increased risk of ovarian cancer for women who had taken antidepressant drugs, even for those taking the most commonly used selective serotonin reuptake inhibitor antidepressants.

For their study, the researchers assessed the past use of all antidepressants, as well as the use of individual classes of antidepressants, in a population-based sample of 593 women with ovarian cancer and 628 control individuals.

In all, 18% of cases reported past use of antidepressants, compared with 20% of controls, indicating that ever use of the drugs does not increase risk for ovarian cancer, at an odds ratio of 0.9. Similarly, the team found no evidence that SSRIs promote ovarian cancer development, with an odds ratio of 1.0, or that such risks rose with duration of use.

The researchers stress the magnitude of their findings, published in the journal Obstetrics and Gynecology.

"Our study had greater than 80% power to detect an odds ratio as small as 1.5," they write. "Thus, even a modest increase in risk with antidepressant use can be excluded with these data."

They conclude: "Given the lack of compelling evidence linking antidepressants and ovarian cancer, the demonstrated benefits of antidepressants in the treatment of depression, premenstrual syndrome, pain, and menopausal symptoms appear to outweigh possible cancer risks associated with their use."


Targeting Mesothelin Shows Promise for Mesothelioma, Pancreatic, and Ovarian Cancers

By Sunil Jani

The development of molecular targeting approaches for the diagnosis and treatment of cancer relies upon the ability to distinguish between normal and cancerous cells. To accomplish this, researchers are in hot pursuit of proteins and receptors that are specifically displayed on the surface of cancer cells but are either not found or are expressed at much lower levels on normal cells. One such target that has shown some early promise for several hard-to-treat cancers is the protein mesothelin. Researchers at NCI, other institutions, and biotechnology companies have been exploring various avenues to utilize mesothelin - a glycoprotein found on the surface of normal mesothelial cells that line the abdominal, lung, and heart cavities - as a target for antibody- and vaccine-based therapies.

"The limited distribution of mesothelin on normal tissues, combined with the fact that it is highly expressed on the surface of many human tumors, makes it an attractive target for tumor-specific therapy," explains Dr. Ira Pastan, chief of the Laboratory of Molecular Biology at the NCI Center for Cancer Research. Most notably, high levels of mesothelin are found in mesothelioma, pancreatic cancer, and ovarian cancer.

Mesothelin also appears to play a role in malignancy, adds Dr. Raffit Hassan, a principal investigator in Dr. Pastan's lab. "These characteristics make it a very important molecule for targeted therapies," he says.

The protein, thought to play a role in cellular adhesion, is also being studied as a cancer vaccine target to trigger a tumor-specific immune response, and as a diagnostic marker to indicate the presence and progression of certain malignancies. Mesothelin was discovered by Drs. Kai Chang, Mark Willingham, and Pastan at NCI; the team then cloned the gene encoding mesothelin, aided by a lab-generated monoclonal antibody, K1, that specifically recognizes mesothelin. Dr. Pastan, with Drs. David Fitzgerald and Partha Chowdhury, took the research a step further, combining the Fv portion of an antibody to mesothelin with a portion of a highly toxic protein, Pseudomonas exotoxin A, to create an immunotoxin called SS1P.

Preclinical studies of SS1P demonstrated antitumor activity against mesothelin-expressing tumors in animal models as well as tumor cells obtained directly from patients with mesothelioma and ovarian cancer. Drs. Robert Kreitman, Hassan, and Pastan are conducting two phase I studies to determine the safety and efficacy of SS1P in patients with advanced cancers whose tumors express mesothelin.

"Preliminary results indicate that SS1P is well tolerated, shows promising clinical activity, and may be useful in patients with small-volume disease who have failed standard chemotherapy," says Dr. Hassan. NCI has entered into a Collaborative Research and Development Agreement (CRADA) with Enzon Pharmaceuticals, Inc., to further develop SS1P for mesothelioma, ovarian, and pancreatic cancers as the immunotoxin moves into phase II trials.

Meanwhile, at the Johns Hopkins Kimmel Cancer Center, Dr. Elizabeth Jaffee and colleagues have had some success with an experimental vaccine that indicates mesothelin could be an important component of a therapeutic vaccine. During a clinical trial using tumor vaccinations for patients with pancreatic cancer, the Hopkins team discovered that three patients had a strong anti-mesothelin T-cell immune response. Six years after vaccination, all three patients are still alive and tumor free. Based on these findings, the researchers have initiated preclinical studies in collaboration with Cerus Corp. to develop a therapeutic listeria-based, mesothelin-targeted cancer vaccine for use against mesothelin-expressing cancers.

Mesothelin also may prove useful in the diagnostic arena. For example, a mesothelin variant has been detected in very small quantities in the blood of patients with malignant mesothelioma and ovarian cancer. A study led by Dr. Ingegerd Hellstrom of the Pacific Northwest Research Institute, showed that the level of these soluble mesothelin-related proteins (SMR) in the blood could potentially be useful to diagnose and measure progression of mesotheliomas. According to their study, 84 percent of patients with mesothelioma had elevated SMR, with increased levels of SMR noted in patients with increased stage and tumor burden. Their results also indicated that SMR could potentially be helpful in screening asbestos-exposed individuals for early evidence of developing mesothelioma. Fujirebio Diagnostics, Inc., is currently trying to develop a commercial diagnostic based on this research.

"Pancreatic cancer and mesothelioma are both aggressive and deadly cancers with no effective treatments currently available," says Dr. Pastan. "The new interventions in development could change that scenario considerably."


AstraZeneca and Aventis Collaboration (Iressa combined with Taxotere® (Docetaxel) or Campto® (Irinotecan)

Summer, 2002:

'Iressa', a once-daily, oral treatment, is a selective inhibitor of an enzyme known as EGFR-TK (epidermal growth factor receptor - tyrosine kinase), a new target for anti-cancer treatments, of which 'Iressa' is foremost in development. 'Iressa' specifically targets and blocks, within the cell, the activity of EGFR-TK, an enzyme that regulates intracellular signaling pathways implicated in cancer cell proliferation and survival. 'Iressa' is being developed by AstraZeneca and is not currently licensed in any country worldwide.

Taxotere is one of the most frequently used and effective chemotherapeutic agents available in the world today. From the taxane class of drugs, Taxotere inhibits cancer cell division by essentially "freezing" the cell's internal skeleton, which is comprised of microtubules. Microtubules assemble and disassemble during a cell cycle. Taxotere promotes their assembly and blocks their disassembly, thereby preventing cancer cells from dividing and resulting in cancer cell death. Campto works by inhibiting the expression of topoisomerase I, an enzyme that is over expressed in malignant colorectal cells. Inhibition of this enzyme's activity blocks the ability of a tumor to grow. Taxotere is marketed globally by Aventis, and the company markets Campto in countries outside the United States.

This research collaboration will explore the effectiveness of combinations of these drugs to treat breast, non-small cell lung cancer, prostate, ovarian, colorectal and gastric cancers.

Pivotal phase ll data demonstrate that 'Iressa' treatment leads to objective response or disease stabilization in many patients with NSCLC who had progressed on previous treatments. In addition, many patients experienced symptom relief within 1-2 weeks of starting treatment. Importantly, the results were achieved without the accompanying side effect burden typically seen with current lung cancer therapies, although mild diarrhoea and skin rash, which are generally reversible, have been reported. These data formed the basis of the regulatory packages for 'Iressa', currently under review by the US Food and Drug Administration (FDA) and the Japanese Ministry of Health, Labour and Welfare (MHLW) for the treatment of advanced non-small cell lung cancer. 'Iressa' is currently completing phase III studies for the first line treatment of NSCLC in combination with chemotherapy and results from these important trials are expected later this year. Since receptors for EGF play a major role in the biology of cancer cells in many solid tumours, 'Iressa' offers potential for the treatment of a broad range of common solid malignancies and has also entered phase II clinical trials in a variety of tumors, including breast, colorectal, head and neck, prostate and gastric cancers.

Taxotere, which is approved worldwide for the treatment of patients with locally advanced or metastatic breast cancer, has demonstrated impressive tumor response rates as well as prolonged survival in these patients. Taxotere is the only taxane approved in Europe for use in combination with doxorubicin for first-line treatment of locally advanced or metastatic breast cancer. Taxotere is also the first and only chemotherapy agent approved worldwide for the treatment of patients with previously treated NSCLC. Campto is a reference treatment for advanced colon cancer. Taxotere and Campto form the backbone of the oncology franchise for Aventis.

"Finding improved treatment alternatives for patients with cancer is the focus of our oncology division," said Dr Belen Garijo, Vice President of Global Oncology at Aventis. "This collaboration will provide another opportunity to aggressively study Taxotere and Campto with an exciting new biological targeting agent."

The collaboration will be jointly funded by the two companies and decisions related to clinical trial design and implementation will be made together through a joint clinical trials committee.




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