ASCO 2011: Genetic Biomarker Predicts Taxane Drug-Induced Neuropathy

A new study has identified the first genetic biomarkers for taxane-induced peripheral neuropathy, a potentially severe complication of taxane chemotherapy that affects nerves in about one-third of patients with cancer receiving such treatment.

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

New study results involving a genetic marker which can predict taxane drug-induced neuropathy were highlighted today in the ASCO press briefing, as summarized below.

Genetic Biomarker Predicts Taxane-Induced Neuropathy

A new study has identified the first genetic biomarkers for taxane drug-induced peripheral neuropathy, a potentially severe complication of taxane chemotherapy that affects nerves in about one-third of patients with cancer receiving such treatment. The finding may eventually lead to a simple blood test to determine whether a patient is at high risk for neuropathy.

Bryan P. Schneider, M.D., Physician & Researcher, Indiana University Melvin & Bren Simon Cancer Center; Associate Director, Indiana Institute for Personalized Medicine

“If these findings can be replicated, this may allow physicians to know prior to recommending therapy whether the patient is at an inordinate risk for developing taxane-induced neuropathy,” said Bryan P. Schneider, M.D., lead author and a physician/researcher at the Indiana University Melvin and Bren Simon Cancer Center and Associate Director for the Indiana Institute for Personalized Medicine. “This may allow for better counseling, use of alternative drugs or schedules, or omission of taxanes in the appropriate settings. These genetic findings might also provide insight into the mechanism of this side effect and help develop drugs to prevent this toxicity altogether.”

Such damage to the nerves can cause pain and numbness and limit the dose of chemotherapy a patient can receive. While only a few factors seem to predict which patients are likely to get peripheral neuropathy, including a history of diabetes and advanced age, genetic variations may explain why some patients are more sensitive to taxane drugs.

The authors conducted a genome wide association study on 2,204 patients enrolled in an Eastern Cooperative Oncology Group breast cancer clinical trial (E5103) in which all patients received taxane-based chemotherapy, namely paclitaxel (Taxol). The study looked for variations in DNA (deoxyribonucleic acid) called single nucleotide polymorphisms, or SNPs (pronounced “snips”), by evaluating more than 1.2 million SNPs in each patient.  A SNP is a DNA sequence variation which occurs when a single nucleotide — A (adenine), T (thymine), C (cytosine), or G (guanine) — in the genome (or other shared sequence) differs between two individuals, or between paired chromosomes located within the nucleus of an individual’s cells.

With a median follow-up of 15 months, the study identified genetic subgroups that were markedly more likely to develop peripheral neuropathy.

Those who carried two normal nucleotides in the RWDD3 gene had a 27 percent chance of experiencing neuropathy; those who carried one normal nucleotide and one SNP had a 40 percent risk; and those who carried two SNPs had a 60 percent risk.

In contrast, those who carried two normal nucleotides in the TECTA gene had a 29 percent chance of experiencing neuropathy; those who carried one normal nucleotide and one SNP had a 32 percent risk; and those who carried two SNPs had a 57 percent risk.

The study also found that older patients and African Americans were much more likely to have peripheral neuropathy, and further analysis of SNPs in these groups is underway.

The authors plan to continue their work in additional trials to validate these findings and to determine whether a different type or schedule of taxane therapy would result in less neuropathy in the more susceptible genetic groups. The authors also are collaborating with neurobiologists to understand why these genetic variations might make the nerves more sensitive to these drugs.

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ASCO 2011: Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors

Cabozantinib (XL184) demonstrated high rates of disease control in patients with prostate, ovarian and liver cancers. The investigators concluded that cabozantinib exhibits clinical activity in ovarian cancer patients with advanced disease, regardless of prior platinum drug status, as reflected by the high rates of response. 

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

The study results from a phase II clinical trial involving cabozantinib (XL184) were highlighted today in the ASCO press briefing, as summarized below.

Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors, and Can Shrink or Eliminate Bone Metastases 

Cabozantinib (XL184) – an oral inhibitor of MET and VEGFR2 kinases involved in the development and progression of many cancers – showed strong responses in patients with various advanced cancers in a phase II trial. The drug demonstrated particularly high rates of disease control for advanced prostate, ovarian and liver cancers, which are historically resistant to available therapies. The drug also fully or partially eliminated bone metastases in patients with breast and prostate cancers and melanoma.

Michael S. Gordon, M.D., President & Chief Executive Officer, Pinnacle Oncology Hematology.

“Cabozantinib appears to have significant effects on several treatment-resistant tumors, as well as impressive effects on bone metastases. In addition, these effects are associated with rapid improvement in pain, a reduction in opiate narcotic requirements and improvement in anemia,” said lead author Michael S. Gordon, M.D., a medical oncologist at Pinnacle Oncology Hematology located in Scottsdale, Arizona. “The implications of these results are very exciting—it is unusual to find a targeted therapy, absent of a molecular mutation in tumors, that works in bony disease and has this activity.”

To be eligible for the study, patients had to have advanced, progressive solid tumors, with or without bone metastases. Of 398 evaluable patients (of 483 enrolled in the trial), 39 percent had bone metastases at baseline. Patients received cabozantinib over 12 weeks. The trial was designed as a “discontinuation” trial, in which those who had partial responses stayed on the drug; those with stable disease were randomized to cabozantinib or placebo; and patients with progressive disease were removed from the trial. This novel type of clinical trial design more quickly evaluates the disease-stabilizing activity of growth-inhibitory agents like cabozantinib, compared to the traditional model of randomizing all patients to either the experimental arm or placebo.

Among 398 patients evaluable with all types of cancer included in the trial, the collective overall response rate was 9 percent (34 of 398). The highest disease control rates (partial response and stable disease) at week 12 were 76 percent for liver cancer (22 of 29 patients), 71 percent for prostate cancer (71 of 100 patients), and 58 percent for ovarian cancer (32 of 51 patients). [emphasis added].

Of the 51 evaluable ovarian cancer patients noted above, 28 are platinum drug resistant, 17 are platinum drug sensitive, and 6 have unknown status. The median number of systemic treatments prior to trial enrollment was 2. The overall response rate (complete response and partial response based on modified RECIST criteria) for ovarian cancer was 12/51 (24%).  Upon breakdown, the response rate was 5/28 (18%) for platinum drug resistant patients, and 5/17 (29%) for platinum drug sensitive patients. Five additional partial responses await confirmation. After a median follow-up of 4 months (range: 1 to 11 months), the median duration of response and median progression free survival have not been reached. The most common related adverse events ( ≥grade 3) among ovarian cancer patients were hand-foot syndrome (10%), diarrhea (8%) and fatigue (4%). Drug dose reductions and permanent discontinuations for adverse events occurred in 43% and 10% of the ovarian cancer patients, respectively. Based on these findings, the investigators concluded that cabozantinib exhibits clinical activity in ovarian cancer patients with advanced disease, regardless of prior platinum drug status, as reflected by the high rates of response. [emphasis added] Accordingly, randomization in the ovarian cancer cohort was halted & patients unblinded due to the observed high efficacy.

Fifty-nine of 68 patients with bone metastases (including patients with breast and prostate cancers and melanoma) experienced either partial or complete disappearance of the cancer on bone scans, often with significant pain relief and other improved cancer-related symptoms.

The reduction of bone metastases and pain relief was an unexpected finding in this study, Dr. Gordon said. Independent review by radiologists confirmed that bone metastases disappeared in the majority of patients who had bone metastases when they entered the study. The majority of these patients had castration-resistant prostate cancer (CRPC), but patients with breast cancer and melanoma also had disappearance of bone metastases. Bone metastases greatly contribute to morbidity and mortality in patients with these types of cancer, which typically spread to the bone.

Due to these results, the study has been expanded to include more CRPC patients. Similarly, the high rate of lasting responses in ovarian cancer patients led researchers to also expand the study to evaluate the drug’s effect on patients with a particularly resistant form of the disease known as platinum drug resistant/refractory ovarian cancer. [emphasis added]

This study expansion results will help determine the design of future phase III trials, which will assess whether the drug extends patients lives or has other longer-term benefits among patients with specific cancer types. At present, cabozantinib is being investigated for use as a single agent. Additional studies will evaluate the efficacy and tolerability of appropriate combinations with other agents for future indications.

For the solid tumor patients collectively, the most common grade three or above adverse events were fatigue (9 percent) and hand-foot syndrome (8 percent). Dose reductions were required in 41 percent of patients due to side effects; 12 percent were removed from the trial for adverse events.

Sources:

Resources:

Cabozantinib (XL184) Clinical Trials:

Related Libby’s H*O*P*E*™ Postings:

ASCO 2011: Maintenance Therapy With PARP Inhibitors Could Play Important Role in Treatment of Recurrent Ovarian Cancer

A randomized phase II clinical trial showed that the oral PARP inhibitor drug olaparib (AZD2281), given after chemotherapy, improved progression-free survival in women with the most common type of recurrent ovarian cancer.

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

The study results from a phase II clinical trial involving maintenance therapy with the PARP (poly (ADP-ribose) polymerase) inhibitor olaparib were highlighted today in the ASCO press briefing, as summarized below.

Randomized Study Shows that Maintenance Therapy With PARP Inhibitors Could Play Important Role in Treatment of Recurrent Ovarian Cancer

A phase II randomized trial showed that maintenance treatment with the oral PARP inhibitor drug olaparib (AZD2281) improved progression-free survival by about four months in women with the most common type of relapsed ovarian cancer. This is the first randomized trial to demonstrate a benefit for maintenance therapy for recurrent ovarian cancer, and the first randomized trial in ovarian cancer of a PARP inhibitor– a novel class of molecularly targeted drugs.

The results of this study, if confirmed in larger trials, could lead to a new treatment approach for recurrent ovarian cancer in which drugs like olaparib are given over a long period of time to prevent recurrences or prolong remissions. This somewhat novel approach, called maintenance therapy, has already proven useful in lung cancer. Standard treatment for ovarian cancer includes platinum-based chemotherapy. After this regimen, patients are observed until recurrence, and then treated with another course of chemotherapy. While some tumors respond well to chemotherapy, the regimens are too toxic for patients to take continuously, and clinical trials have not shown any benefit for extended courses of chemotherapy.

Jonathan A. Ledermann, M.D., Lead Author & Principal Investigator of PARP Maintenance Study; Professor, Medical Oncology, UCL Cancer Institute, University College London

“A well-tolerated antitumor agent that could be used for months or perhaps years as maintenance therapy after standard chemotherapy could be a big step forward and ultimately extend survival,” said lead author Jonathan A. Ledermann, M.D., principal investigator of the study and Professor of Medical Oncology at UCL Cancer Institute, University College London. “This study demonstrates proof of principle for the concept of maintenance therapy in ovarian cancer using a PARP inhibitor. Our progression-free survival difference was very impressive and better than we anticipated.”

The multicenter, international study randomized 265 women with high-grade serous ovarian cancer to either olaparib or placebo. Patients were enrolled in the trial within 8 weeks of having achieved either a complete or partial response to platinum-based treatment. PARP inhibitors have been shown to work better in patients whose tumors have responded to platinum.

In the study, the progression-free survival (PFS) – the amount of time during and after treatment in which the cancer does not return – was significantly longer in the group receiving olaparib than the placebo group, with a median of 8.4 months versus 4.8 months. At the time of data analysis, half the patients randomized to olaparib (68 patients) had not relapsed and were still receiving the drug, while only 16 percent (21 patients) remained on placebo – so overall survival data were not yet available for analysis.

Adverse events were more commonly reported in the group receiving olaparib than placebo, including nausea, fatigue, vomiting, and anemia, but the majority of these were not severe. Dose reductions to manage side effects were allowed in the study and were more prevalent in the olaparib group (23 percent) compared to the placebo group (7 percent).

Olaparib inhibits the enzyme poly (ADP-ribose) polymerase — abbreviated “PARP” — which is involved in DNA (deoxyribonucleic acid) repair. Up to half of women with high-grade serous ovarian cancer – the most common type of ovarian cancer – may have a DNA repair deficiency that makes them more susceptible to treatment with PARP inhibitors.

A number of PARP inhibitors are being studied in phase II and phase III clinical trials, as single agents and in combination with standard chemotherapies and radiation, in some types of breast and ovarian cancers believed to have DNA repair defects.

Sources:

PARP Clinical Trials:
Resources:
Related WORD of HOPE™ Ovarian Cancer Podcasts:
Related Libby’s H*O*P*E*™ Postings:
Related Libby’s H*O*P*E*™ Videos Re PARP Inhibitors


2011 ASCO: Screening With CA-125 & Transvaginal Ultrasound Does Not Reduce Ovarian Cancer Death Rate, Results in High Number of False Positives

Findings from a large, long-term study – the Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial – showed that using a CA-125 blood test and transvaginal ultrasound for early detection of ovarian cancer did not reduce the risk of dying from the disease, and resulted in a large number of false positives and related follow-up procedures.

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Ill. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

The study results from a large clinical trial involving ovarian cancer screening were highlighted in today’s press briefing as summarized below.

Screening with CA-125 and Transvaginal Ultrasound Does Not Reduce Ovarian Cancer Death Rate, Results in High Number of False Positives

A randomized, multicenter screening study of nearly 80,000 women in the general population showed that using a CA-125 blood test and transvaginal ultrasound for early detection of ovarian cancer did not reduce the risk of dying from the disease, and resulted in a large number of false positives and related biopsies and follow-up procedures. The results indicate that while these tests are widely and appropriately used to evaluate symptoms, and to gauge disease status and effectiveness of treatment in women already diagnosed with ovarian cancer, they are not useful in screening the general population.

Saundra S. Buys, M.D., Medical Director, Huntsman Cancer Institute’s High Risk Breast Cancer Clinic; Professor, Depart. of Internal Medicine, Univ. of Utah School of Medicine

“There hasn’t been a good method for the early detection of ovarian cancer, and our hypothesis was that CA-125 and transvaginal ultrasound, which are useful in measuring disease, would also identify ovarian cancer early, at a stage in which it is more likely to be cured,” said lead author Saundra Buys, M.D., professor of medicine at the University of Utah and Huntsman Cancer Institute in Salt Lake City. “The results were disappointing, but not necessarily surprising. The study shows that the available tests are not effective and may actually cause harm because of the high number of false positives. These results point to the continued need for more precise and effective screening tools for this disease.”

In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 78,216 women ages 55 to 74 were assigned to either annual screening (39,105 women) or usual care (39,111 women) between 1993 and 2001. Women in the screening arm were offered annual CA-125 testing for six years and transvaginal ultrasound for four, and followed for up to 13 years. Those in the usual care arm were not offered the screening tests.

The results showed no statistically significant difference in ovarian cancer cases or mortality between the two arms. Ovarian cancer was diagnosed in 212 women in the screening group arm compared to 176 in the usual care arm; 118 women in the screening arm died from ovarian cancer, while 100 died from ovarian cancer in the usual care group.

Among women in the screening arm, there were a high number of false positives – 3,285 false positives, compared to just 212 true positives. Of women who had a false positive test, 1,080 underwent surgery for biopsy – the procedure generally required to evaluate positive test results; 163 of them had serious complications.

The authors emphasized that the study results don’t apply to screening women with symptoms or abnormal findings on physical examination. [emphasis added] Physical examination based on symptoms and appropriate follow-up testing remains the best available approach for ovarian cancer detection.

[Note: This summary contains updated data and a correction from the original abstract. Correction:  Of the 3,285 women who received a false positive exam, 1,080 underwent surgery. Of those surgical patients, 163 encountered at least one serious complication.]

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2011 ASCO Annual Meeting Abstracts (Including Ovarian Cancer) Made Publicly Available Today

More than 30,000 cancer specialists from around the world will gather at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting to discuss the latest innovations in research, quality, practice and technology in cancer.

More than 30,000 cancer specialists from around the world will gather at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting to discuss the latest innovations in research, quality, practice and technology in cancer.

The meeting will be held June 3-7, 2011 at McCormick Place located in Chicago, Illinois. This meeting will be the platform for the release of thousands of scientific abstracts — highly anticipated research news for many people, including patients, caregivers, and the general public. Today, many of those abstracts were made publicly available online (see below).

The 2011 Annual Meeting will center on a theme of “Patients, Pathways, Progress.” The theme, which was selected by ASCO President George W. Sledge, Jr., M.D., promises to:

  • Represent “patients first,” said Dr. Sledge. “Everything we do as a Society has, as its eventual goal, the reduction of cancer mortality and morbidity. We’re on the front line in the war against cancer.”
  • Focus on the molecular, clinical and research pathways that are used to find, develop and implement new treatments for people living with cancer.
  • Celebrate the progress that has already been made in the treatment of cancer, while also reaffirming ASCO’s commitment to aggressive advancements in cancer research in the future.
News announced during the Annual Meeting will include the latest findings from cancer clinical trials, including new drug studies that could change current standards of care. ASCO shares this timely information with the public in a variety of ways. Free patient-friendly summaries of research news highlights from this year’s Annual Meeting will be available via ASCO’s patient information website, Cancer.Net (www.cancer.net). Cancer.Net will post scientific news as soon as it becomes publicly available, on both its homepage and its ASCO Annual Meetings section. The offerings on Cancer.Net include:
  • Easy-to-read summaries that put the top scientific news into context for patients.
  • Videos and podcasts of national and international cancer experts, breaking down the science into specific disease areas and explaining what the studies mean for people with cancer.
  • A news archive from previous ASCO Annual Meetings, which is searchable by year or disease type.

To receive ASCO Annual Meeting breaking news via email, you can sign up now to receive special editions of the newsletter Inside Cancer.Net. You can also follow Cancer.Net on Facebook or Twitter, where real-time updates will also be posted.

Medical abstracts from this year’s meeting were released today at 6:00 P.M. EDT/3:00 P.M. PDT, and additional studies will be released each day of the event in June.

The abstract categories released today, which may be of interest to an ovarian cancer survivor, include the following:

Cancer Prevention/Epidemiology

Developmental Therapeutics – Clinical Pharmacology and Immunotherapy

Gynecologic Cancer

2011 Pharmaceutical Research & Manufacturers of America Report Lists 58 Drugs in Development For Ovarian Cancer

Currently, 851 medicines are in development for diseases that exclusively or disproportionately affect women, according to a report unveiled today by the Pharmaceutical Research and Manufacturers of America (PhRMA).

Currently, 851 medicines are in development for diseases that exclusively or disproportionately affect women, according to a report unveiled today by the Pharmaceutical Research and Manufacturers of America (PhRMA).  The medicines in the pipeline for women (either in human clinical trials or awaiting review by the Food and Drug Administration) include:

• 139 for cancers affecting women, including 91 for breast cancer, 49 for ovarian cancer,[1] and 9 for cervical cancer.

• 114 for arthritis/musculoskeletal disorders. Approximately 46 million Americans have some type of arthritis or related condition, and 60 percent of them are female.

• 64 for obstetric/gynecologic conditions.

• 110 for autoimmune diseases, which strike women three times more than men.

• 72 for depression and anxiety. Almost twice as many women as men suffer from these disorders.

• 83 for Alzheimer’s disease. Two-thirds (3.4 million) of the 5.4 million Americans living with Alzheimer’s today are women.

The Drug Discovery Process

Ovarian cancer affected an estimated 21,880 U.S. women in 2010 and caused an estimated 13,850 deaths.  The PhRMA report highlighted a potential first-in-class ovarian cancer drug (volasertib/BI 6727) in development which works by selectively inhibiting the polo-like kinase-1 (PLK-1), an enzyme crucial for cell division. PLK-1 is expressed in proliferating cells and most tumors. Inhibiting its activity disrupts cell division, which induces cell death and reduces cancer growth.

The ovarian cancer drugs listed in the PhRMA report are listed below by name (brand name, if available, and generic name), manufacturer, and phase of clinical testing. The ovarian cancer drugs listed in the “Cancer” section of the PhRMA report are set forth below:[2]

A6, Angstrom Pharmaceuticals, Phase II.

Abagovomab (anti-idiotype ovarian cancer vaccine)(Orphan Drug), Menarini, Phase I/II.

Abraxane®/albumin-bound paclitaxel, Celgene, Phase II.

ABT-888/veliparib, Abbott Laboratories, Phase II.

AE-37, Antigen Express, Phase I.

Afinitor®/everolimus, Novartis Pharmaceuticals, Phase I/II.

AMG 386, Amgen, Phase III.

AMG 479, Amgen, Phase II.

Avastin®, bevacizumab, Genentech, Phase III.

BC-819, BioCancell Therapeutics, Phase I/II.

Catumaxomab, Fresenius Biotech, Phase II.

CVac™/MUC-2 cancer vaccine, Prima BioMed, Phase II.

DCVax®-L/ovarian cancer vaccine, Northwest Biotherapeutics, Phase I.

DPX-0907, Immunovaccine, Phase I.

EC-145, Endocyte, Phase II.

EGEN-001 (Orphan Drug), EGEN, Phase I/II.

ENMD-2076, EntreMed, Phase II.

Estybon™/ON-01910.Na, Onconova Therapeutics, Phase II.

Evizon™/squalamine, OHR Pharmaceuticals, Phase II.

farletuzumab/MORAb-003, Eisai, Phase III.

iboctadekin, GlaxoSmithKline, Phase I.

IMT-1012/immunotherapeutic vaccine, Immunotope, Phase I.

iniparib/BSI-201, BiPar Sciences/sanofi-aventis, Phase II.

Karenitecin®/cositecan, BioNumerik Pharmaceuticals, Phase III.

KHK-2866, Kyowa Hakko Kirin Pharma, Phase I.

lenvatinib/E7080, Eisai, Phase II.

MK-2206, Merck, Phase I.

Nexavar®/sorafenib, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals, Phase II.

NKTR-102, Nektar Therapeutics, Phase II.

NOV-002, Novelos Therapeutics, Phase II.

OGX-427, Oncogenex Pharmaceuticals, Phase I.

olaparib/AZD2281, AstraZeneca, Phase II.

Opaxio™/paclitaxel poliglumex, Cell Therapeutics/Novartis Pharmaceuticals, Phase III.

Optisome™/topetecan liposomal, Talon Therapeutics, Phase I.

Oregovomab, Quest Pharmatech, Phase I/II.

OSI-906/linsitinib, OSI Pharmaceuticals, Phase II.

OVax®/ovarian cancer vaccine (Orphan Drug), AVAX Technologies, Phase I/II.

Perifosine/KRX-0401, AEterna Zentaris/Keryx Biopharmaceuticals, Phase I.

PF-01367338, Pfizer, Phase II.

Phenoxodiol (next generation drug will be NV-143), Marshall Edwards, Phase III.

Picoplatin intravenous, Poniard Pharmaceuticals, Phase II.

Quinamed®/amonafide, ChemGenex Pharmaceuticals, Phase II.

Ramucirumab/IMC-1121-B, Eli Lilly/ImClone, Phase I.

Ridaforolimus, Merck/Ariad Pharmaceuticals, Phase I.

Sagopilone, Bayer HealthCare Pharmaceuticals, Phase II.

SAR256212/MM-121, Merrimack Pharmaceuticals/sanofi-aventis, Phase I.

SG2000, Spirogen, Phase II.

Sprycel®/dasatinib, Bristol-Myers Squibb, Phase

Tarceva®/erlotinib, Genentech, Phase II.

Telcyta®/canfosfimide, Telik, Phase III.

Tigatuzumab, Daiichi Sankyo, Phase II.

Tykerb®/lapatinib, GlaxoSmithKline, Phase I/II.

Volasertib, Boehringer Ingelheim Pharmaceuticals, Phase II.

Volociximab, Bigen Idec/Facet Biotech, Phase II.

Vosaroxin™/SNS-595, Sunesis Pharmaceuticals, Phase II.

Votrient®/pazopanib, GlaxoSmithKline, Phase III.

Zolinza®/vorinostat, Merck, Phase II.

Zybrestat™/fosbretabulin, OXiGENE, Phase II.

References:

1/The 2011 PhRMA report lists 49 ovarian cancer drugs in development.  After comparing the entire “Cancer” drug list set forth on pages 16 – 24 of the PhRMA report to the ovarian cancer clinical trials provided at http://www.clinicaltrials.gov, we determined that an additional nine drugs appearing on the PhRMA cancer drug list are being tested in ovarian cancer clinical trials.

2/Please note that the PhRMA cancer drug list does not set forth all ovarian cancer drugs in development.  For a list of all open ovarian cancer clinical trials listed at www.clinicaltrials.gov, click here.

Sources:

Resources:

Blunting the Activity of Protein Abcc10 May Help Counter Taxane Drug Resistance In Ovarian Cancer

New findings by Fox Chase Cancer Center researchers identify one protein, Abcc10, as being intimately involved in resistance to certain drugs used to treat breast, ovarian, lung, and other cancers. The results suggest that blunting the activity of Abcc10 might help counter resistance and extend the effectiveness of these anticancer drugs.

Today’s anticancer drugs often work wonders against malignancies, but sometimes tumors become resistant to the effects of such drugs, and treatment fails. Medical researchers would like to find ways of counteracting such resistance, but first they must understand why and how it happens. New findings by Fox Chase Cancer Center researchers identify one protein, Abcc10 (ATP-binding cassette transporter 10) (also known as multidrug resistance protein 7 (Mrp7)), as being intimately involved in resistance to certain drugs used to treat breast, ovarian, lung, and other cancers. The results suggest that blunting the activity of Abcc10 might help counter resistance and extend the effectiveness of these anticancer drugs.

The findings appear in the May 15, 2011 issue of the journal Cancer Research.

Elizabeth A. Hopper-Borge, Ph.D., Assistant Professor, Fox Chase Cancer Center, Philadelphia, Pennsylvania

In earlier work, Elizabeth A. Hopper-Borge, Ph.D., an assistant professor at Fox Chase, showed that Abcc10 confers resistance to a number of anticancer agents, particularly taxanes, which include paclitaxel (Taxol) and docetaxel (Taxotere). These drugs––originally derived from the Pacific yew tree––work by disrupting cell division, thus arresting the growth and spread of tumors. The initial finding that Abcc10, a member of a ubiquitous family of proteins called ATP-binding cassette transporters, thwarts taxanes’ anti-tumor activity was something of a surprise, says Hopper-Borge, because none of the other family members seem to have that ability.

In the new research, Hopper-Borge and colleagues wanted to further explore, in both cultured cells and mice, the role of Abcc10. They developed a “knockout” mouse, in which the gene that codes for Abcc10 was missing, or knocked out. These mice appeared normal and healthy in every other respect, suggesting that Abcc10 is not essential for overall health and survival.

The researchers isolated cells from the knockout mice and tested the cells’ reactions to taxanes and two other anticancer drugs, vincristine and Ara-C. Compared to cells from normal mice that still possessed the gene for Abcc10, the knockout mouse cells were much more sensitive to the drugs.

Abcc10 and its ilk work by pumping drugs out of cells, so one might expect to see the drugs accumulating in cells that lack Abcc10, and that’s exactly what Hopper-Borge’s group saw. It had been suggested that other proteins might take over for Abcc10 if that protein were knocked out, but the researchers found no evidence suggesting that had happened.

Next, the research team studied the effects of one particular taxane, paclitaxel, on mice and found that the knockout mice were more sensitive to the drug, as reflected in body weight, white blood cell count, and ability to survive escalating doses of the drug.

“After seeing the effects on white blood cells, we decided to look at the tissue types that produce white blood cells to see if we could actually see differences there,” says Hopper-Borge. As expected, knockout mice treated with paclitaxel had smaller spleens and thymus glands and underdeveloped bone marrow, compared to normal mice treated with the same drug.

The results provide the first evidence from living organisms that Abcc10 is a cell’s built-in protection against the effects of powerful drugs, and raises the possibility of using Abcc10 inhibitors to break down that resistance and sensitize tumor cells to anticancer agents. The fact that mice lacking the protein have no obvious health problems is encouraging, suggesting that Abcc10 inhibitors could be used in human patients without causing side effects that might be expected to result from interfering with the pump’s normal functions.

Several Abcc10 inhibitors already have been identified, but they also inhibit other cellular transporters, which could have deleterious effects. For that reason, Hopper-Borge thinks the best approach may be developing inhibitors that work only in tumor cells or coming up with compounds that modulate, rather than completely inhibit the protein’s activity.

But using such treatments in patients is still far in the future, she emphasizes.

“I’d like to stress that we did this work in a mouse model,” Hopper-Borge says. “Our results so far suggest that this protein may be a clinically relevant target, but we need to do more studies to find out for sure.”

Co-authors on the study include Timothy Churchill, Chelsy Paulose, Emmanuelle Nicolas, Joely D. Jacobs, Olivia Ngo, Andres J. Klein-Szanto and Martin G. Belinsky of Fox Chase; Yehong Kuang of Central South University, Changsha, China; Alex Grinberg and Heiner Westphal of the National Institute of Child Health and Human Development; and Gary D. Kruh of the University of Illinois at Chicago.

The research was supported by the National Institutes of Health.

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