Archive for the ‘Sarcoma’ Category

Tumorpedia Apps

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Posted 11 Jun 2012 — by James Street
Category Chondrosarcoma, Diagnostic, Online Research Tools, Osteosarcoma, rhabdomyosarcoma, Sarcoma

Do you need all accurate, up-to-date tumor information on your mobile device? Now you can get the Tumorpedia apps! Tumorpedia – Lite is your free mobile source for musculoskeletal tumor information. See all the Tumorpedia apps for in-depth information on this topic.

The Tumorpedia apps give you immediate, on-the-go access to up-to-date information on all the most common (and not so common) benign and malignant musculoskeletal tumors, such as osteosarcoma, enchondroma, lipoma, and more. Includes presentation, incidence, images, pathology, DDX, and treatment for each tumor.

Tumorpedia is designed for physicians, surgeons, radiologists, pathologists, primary care providers, podiatrists, residents, interns, medical students, and patients as well. Tumorpedia is available for iPhone and iPad and Android mobile devices.

The Tumorpedia applications give you rapid mobile access to the most comprehensive medical information covering all aspects of benign and malignant bone and soft tissue tumors, foot and ankle tumors, and musculoskeletal tumor information in Spanish.

Tumorpedia comprises a suite of mobile applications focusing on different types of tumors. The applications include Tumorpedia-lite, our free version, and the comprehensive companion application – Tumorpedia-bone, Tumorpedia-soft tissue, Tumorpedia-foot and ankle, and Tumorpedia-Espanol, designed for Spanish-language users.

Each Tumorpedia app contains information on 20 to 50 different tumors, covering the etiology, pathogenesis, clinical presentation, and examination findings, as well as the xray, MRI, and CT scan appearance of the tumor. The diagnostic features of each tumor are illustrated with hundreds of images from actual case examples. In addition, the microscopic pathology findings are described and illustrated. The app provides treatment options, outcomes information, and prognosis for each tumor.

There is no textbook in print that has the information available in this application, presented in the manner that it is. It’s a great tool for orthopedic surgeons, radiologists, pathologists, podiatrists, residents and students who might be caring for patients with these tumors.

It’s hard to memorize the variable presentations and diagnostic features of these tumors, which can range anywhere from minor, benign conditions to serious, aggressive cancers. Zeroing in on the right diagnosis is really essential in determining the most accurate and appropriate tests to use. Having this information readily available, right at the point of care is invaluable.

Inhibitory effect of Greenland shark liver oil combined with squalen and arctic birch ashes on angiogenesis and L-1 sarcoma growth in Balb/c mice.

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Posted 06 Jun 2012 — by James Street
Category Osteosarcoma, rhabdomyosarcoma, Sarcoma, Shark Liver Oil
Pol J Vet Sci. 2003;6(3 Suppl):54-6.

Source

Dept. Lab. Diagnostics and Immunology, National Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, 26 Płocka street, Poland. ewaskop@hotmail.com

Abstract

Sharks have been claimed to be resistant to cancer and oil from their livers have been used in Scandinavian folk medicine as anti-tumor drug. Shark liver oil contains 40% or more of squalene. Fish liver oil is also rich in squalene and polyunsaturated n-3 fatty acids. The aim of this work was to determine the anti-angiogenic and anti-tumor effects of these substances, together with another Scandinavian traditional remedy–arctic birch ashes–in Balb/c mice after transplantation of syngeneic L-1 sarcoma. All substances tested, alone or in combinations, significantly diminished cutaneous angiogenesis induced by tumor cells, and tumor growth.

PMID:
14509365
[PubMed - indexed for MEDLINE]

LinkOut – more resources

FDA approves Votrient for advanced soft tissue sarcoma

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Posted 05 Jun 2012 — by James Street
Category Sarcoma, Votrient (pazopanib)

DA NEWS RELEASE

For Immediate Release: April 26, 2012
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

The U.S. Food and Drug Administration today approved Votrient (pazopanib) to treat patients with advanced soft tissue sarcoma who have previously received chemotherapy. Soft tissue sarcoma is a cancer that begins in the muscle, fat, fibrous tissue, and other tissues.

Votrient is a pill that works by interfering with angiogenesis, the growth of new blood vessels needed for solid tumors to grow and survive.

A rare cancer with many subtypes, soft tissue sarcoma occurs in about 10,000 cases annually in the United States. More than 20 subtypes of sarcoma were included in the clinical trial leading to approval of Votrient. The drug is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors.

“Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Drug development for sarcomas has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas.”

The safety and effectiveness of Votrient was evaluated in a single clinical study in 369 patients with advanced soft tissue sarcoma who had received prior chemotherapy. Patients were randomly selected to receive Votrient or a placebo. The study was designed to measure the length of time a patient lived without the cancer progressing (progression-free survival). The disease did not progress for a median of 4.6 months for patients receiving Votrient, compared with 1.6 months for those receiving the placebo.

The most common side effects in Votrient-treated patients were fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.

Votrient carries a boxed warning alerting patients and health care professionals to the potential risk of liver damage (hepatotoxicity), which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines.

Votrient was granted an orphan drug status designation for this indication. An orphan designation is given to a drug intended to treat a disease affecting fewer than 200,000 patients in the United States. Votrient was first approved in October 2009 for the treatment of advanced kidney cancer.

Votrient is marketed by GlaxoSmithKline of Research Triangle Park, N.C.

For more information:

FDA: Office of Hematology and Oncology Products

FDA: Approved Drugs: Questions and Answers

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Moffitt Cancer Center researchers identify drivers of sarcoma growth and survival

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Posted 06 May 2012 — by James Street
Category Kinase, Osteosarcoma, Proteomics, Sarcoma, Tyrosine Kinase

Posted On: May 1, 2012 – 9:00pm

To better understand the signaling pathways active in sarcomas, researchers at Moffitt Cancer Center used state-of-the-art mass spectrometry-based proteomics to characterize a family of protein enzymes that act as “on” or “off” switches important in the biology of cancer. The tyrosine kinases they identified, the researchers said, could act as “drivers” for the growth and survival of sarcomas.

Sarcomas are relatively rare forms of cancer. In contrast to carcinomas, which arise from epithelial cells (in breast, colon and lung cancers, for example), sarcomas are tumors derived from bone, fat, muscle or vascular tissues.

“Sarcomas are rare, diverse malignancies that arise from connective tissues,” said study lead author Eric B. Haura, M.D., program leader for Experimental Therapeutics. “We hypothesized that we could identify important proteins that drive the growth and survival of these poorly understood sarcomas using an approach to characterize signaling proteins using mass spectrometry.”

According to Haura, whose lab focuses on signaling pathways in cancer and understanding the role of kinases, protein phosphorylation plays a significant role in a wide range of cellular processes and is commonly disrupted in diseases such as cancer. The study approach is novel by engaging proteomics, an emerging and increasingly powerful approach to study proteins in disease in a more global and unbiased manner.

In this study, the Moffitt researchers identified 1,936 unique tyrosine phosphorylated peptides corresponding to 844 unique phospho-tyrosine proteins and found 39 tyrosine kinases in sarcoma cells. Of the 99 tyrosine kinases present in the human genome, the research team identified peptides corresponding to nearly 40 percent of the tyrosine kinome.

“Tyrosine kinases play an important role in controlling the hallmarks of cancer, and they have a proven track record as druggable targets for cancer treatment. Our goal was to produce a ‘landscape’ of tyrosine phosphorylated proteins and tyrosine kinases prioritized for subsequent functional validation,” Haura said. “In our study, we identified numerous tyrosine kinases that can be important for cellular signaling in human sarcomas that could drive the natural progression of sarcoma and, therefore, could be targeted by small molecule inhibitors aimed at altering sarcoma progression.”

Questions remain, however, about which, if any, of the 40 tyrosine kinases the researchers identified in sarcoma tumor cell lines act to regulate sarcoma tumor cell growth and tumor survival.

“The answers to this question can help prioritize which potential targets to examine further, including advancement into trials of patients with advanced sarcoma,” explained Haura. “As a first step, we screened sarcoma cell lines against a number of inhibitors selected, all based on the tyrosine kinases we identified, and identified some active drugs.”

While the researchers found kinases in sarcoma cells that deserved further study, they also concluded that the sarcoma cells tested expressed multiple tyrosine kinases. That great number may limit the effectiveness of targeted agents.

“We think this approach could hold promise in profiling tumors directly from patients and can complement existing genetic data on sarcomas. Our results show this is feasible in tumor tissues, and we hope to advance this further by directly studying additional tumors from sarcoma patients.”

 

FDA Approves GSK Cancer Drug Votrient For Soft-Tissue Sarcoma

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Posted 28 Apr 2012 — by James Street
Category Sarcoma, Votrient
  • April 26, 2012, 8:02 p.m. ET

WASHINGTON (Dow Jones)–The Food and Drug Administration on Thursday approved GlaxoSmithKline PLC’s (GSK, GSK.LN) cancer drug Votrient for use in patients with soft-tissue sarcoma, making it the first new treatment for the rare type of cancer in decades.

Votrient, a tablet taken orally, is already on the U.S. market to treat advanced kidney cancer. It was approved to treat several subtypes of advanced soft-tissue sarcoma, after prior chemotherapy. The disease starts in muscle or other connective tissues in the body.

The National Cancer Institute estimates there are about 11,000 cases of soft-tissue sarcomas diagnosed in the U.S. each year.

Votrient’s approval follows the March recommendation of an agency advisory panel, which voted, 11-2, that the drug’s benefits outweighed the risks. Clinical data involving 369 patients showed the drug temporarily slowed tumor growth.

Specifically, the study showed patients being treated with Votrient had a median progression-free survival of 4.6 months compared with 1.6 months on the placebo, or a difference of three months in the time before the cancer starts to worsen.

The FDA noted that Votrient carries the agency’s toughest boxed warning, telling patients and health-care professionals about the potential risk of liver damage, which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines, the agency said.

The most common side effects seen in Votrient-treated patients were fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration, the FDA said.

-Jennifer Corbett Dooren, Dow Jones Newswires; 202-862-9294; jennifer.corbett@dowjones.com

$250K Grant Funds a Global Collaborative Research Study on Myxoid Liposarcoma

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Posted 15 Apr 2012 — by James Street
Category General Cancer Research, liposarcoma (myxoid), Sarcoma
PRWeb
Published 12:00 p.m., Wednesday, April 11, 2012

Press Release

Researchers from three countries join forces and share resources in order to gain new insights into myxoid liposarcoma and its treatment.

Ossining, New York (PRWEB) April 11, 2012

The Liddy Shriver Sarcoma Initiative has awarded a $250,000 grant to fund a new collaborative research study on myxoid liposarcoma. The grant brings together researchers from Canada, the Netherlands and the United States in a two-year study of this rare cancer.

Myxoid liposarcomas account for about 10% of all soft tissue sarcomas, which are rare cancers of the connective tissues. They typically affect adults between the ages of 30 and 50 years old and are prone to metastasize (spread throughout the body). There are currently no effective systemic therapies for the disease, which can be highly lethal.

One of the difficulties in studying rare diseases is a lack of resources, specifically tissue specimens and patient data. This study addresses that challenge by creating the world’s largest collection of primary tumor samples and cell models of myxoid liposarcoma, a resource that will be made available to qualified researchers worldwide.

Dr. Torsten Nielsen says, “We’re combining resources from multiple countries to get enough samples of a relatively rare disease that we can make sense out of them — a scientifically large enough collection.”

Investigators will then use tissue samples to better understand myxoid liposarcoma and its response to various treatments. They will also work to identify pathways that can be targeted with existing and experimental drugs.

According to Dr. Nielsen, there is definite promise in this research: “In myxoid liposarcoma, we know that there is a very specific, causative mutation called FUS-DDIT3. The scientific community has yet to translate this finding into new therapies for patients — partly because there have not been enough researchers working on it, and partly because no one research team has access to enough materials (cancer cells and tumor specimens) to do this work effectively. I believe that with this funding we have a great opportunity to connect the underlying molecular biology to new treatment opportunities.”

According to Dr. Dina Lev, studies like this one are often inspired by physicians’ interactions with their patients: “Personal experience in caring for myxoid liposarcoma patients, including the opportunity, unfortunately, to directly observe therapeutic failure, has been and continues to be a powerful motivation to pursue these research opportunities.”

The study’s investigators hope to learn enough about the disease to improve its treatment. Dr. Judith Bovée explains: “The aim is to better understand the development of myxoid liposarcoma, which will contribute to ‘personalized’ or tailor-made medicine: each patient will receive the most optimal treatment for his or her tumor.”

THE COLLABORATIVE MODEL
Cancer research can be a highly competitive field, but sarcoma researchers share a unique sense of teamwork within the cancer research community. Dr. Nielsen explains, “Sarcoma researchers have a real sense of community and cooperation. Sometimes it feels like there are more types of sarcoma than there are sarcoma research teams! We are keenly aware that we need to combine resources to achieve critical mass for the study of rare diseases.”

Funding from the Liddy Shriver Sarcoma Initiative will enable these four researchers to collaboratively employ their resources and make more progress than each investigator can make individually. By working as an international team with complementary strengths, each team member can focus his or her skills to address specific questions while also contributing to a larger project that is both scientifically tractable and clinically relevant.

Dr. Lazar believes that this grant is a model for rare disease research: “This type of structure is a very good model for studying rare diseases and has been used successfully for studying sarcomas in the Children’s Oncology Group in the US and in various European jurisdictions as well.”

There can even be unexpected benefits of global collaboration. Dr. Lazar notes that grants like this one “help to create patterns of interaction between the participants that will likely lead to unanticipated future discoveries and advances solely because of the unique conditions created from the collaboration.”

Bruce and Beverly Shriver, co-founders of the Liddy Shriver Sarcoma Initiative, are committed to providing a unique source of support for global initiatives in sarcoma research. They explain, “The approach we are taking with our International Collaborative Grants program brings quality researchers and clinicians together to help find cures for these rare cancers. What is particularly exciting is that the new myxoid liposarcoma research team will be meeting to share insights with the research team we funded in well-differentiated and de-differentiated liposarcoma a year and a half ago.”

THE FUNDING
This grant was made possible by generous donations in support of the Wendy Walk. Wendy Landes’ three children, Ali, Matt and Jackie, created the Wendy Walk in 2010 after their mother was diagnosed with multi-focal dedifferentiated liposarcoma. Ali, Matt and Jackie were inspired by Wendy’s strength, courage, faith, and unwavering positive attitude, and they wanted to increase liposarcoma awareness and raise funds to support liposarcoma research. Together the Landes family has raised more than $450,000 to date, and their dedicated efforts continue. The Wendy Walk will be held in three cities this spring:

  •     Miami, Florida: April 14th
  •     New York City: April 29th
  •     Los Angeles: May 6th

About the Investigators
Each investigator involved in this study has an established infrastructure of equipment, specimens, models, and supporting personnel for sarcoma research. In addition, each member of the research team has demonstrated a track record of productivity and accomplishment in studying liposarcoma. Investigators include:

  • Judith Bovée, MD, PhD, a pathologist and associate professor in the Department of Pathology at Leiden University Medical Center. Her focus is on translational sarcoma research, for which she has several grants from the Netherlands Organization for Scientific research (NWO) and the KWF Dutch Cancer Society.
  • Alexander Lazar, MD, PhD a faculty member in the Sarcoma Research Center at the University of Texas MD Anderson Cancer Center (UTMDACC). Dr. Lazar’s particular expertise lies in tissue-based translational research, molecular diagnostics and early genetic changes in sarcoma.
  • Dina Lev, MD, the principal investigator of the Sarcoma Research Laboratory (SRL) at UTMDACC. The SRL provides unique access to a large number of sarcoma patient derived samples, permitting the development of human sarcoma experimental models. Dr. Lev’s research focuses on the identification of molecular markers and therapeutic targets for a range of soft tissue malignancies.
  • Torsten Nielsen, MD, PhD, a clinician-investigator pathologist at the University of British Columbia, Vancouver. Dr. Torsten runs research labs active in translating novel molecular findings into practical diagnostics and new treatments. His work has already led to two new, widely-used diagnostic biomarkers in sarcoma and to two clinical trials that are currently underway.

About the Liddy Shriver Sarcoma Initiative
The Liddy Shriver Sarcoma Initiative is a small organization dedicated to increasing global public awareness of sarcoma, raising funds to award research grants, and providing support and timely information to sarcoma patients, their families, and medical professionals. The International Collaborative Grant program is an integral part of the Liddy Shriver Sarcoma Initiative’s philosophy: that improved outcome for sarcoma patients can best be made by teams of dedicated investigators working collaboratively and cohesively.This grant was approved through the Initiative’s unique peer-review process. A comprehensive experimental plan for the study has been published in April’s issue of the Electronic Sarcoma Update Newsletter, and a study report will be published when the project is completed.

For the original version on PRWeb visit: http://www.prweb.com/releases/prweb2012/4/prweb9383687.htm

FDA Staff Questions Benefits of Glaxo, Merck Cancer Drugs

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Posted 18 Mar 2012 — by James Street
Category Ridaforolimus, Sarcoma, Votrient (pazopanib)

By Anna Edney – Mar 16, 2012 1:09 PM PT

Trabectedin, From Wikipedia, the free encyclopedia

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Posted 16 Mar 2012 — by James Street
Category ecteinascidin (ET-743), Osteosarcoma, Sarcoma, Trabectedin, Yondelis

Trabectedin (also known as ecteinascidin 743 or ET-743) is an anti-tumor drug. It is sold by Zeltia and Johnson and Johnson under the brand name Yondelis. It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and ovarian cancer.

Contents

[hide]

[edit] Discovery and development

During the 1950s and 1960s, the National Cancer Institute carried out a wide ranging program of screening plant and marine organism material. As part of that program extract from the sea squirt Ecteinascidia turbinata was found to have anticancer activity in 1969.[1] Separation and characterisation of the active molecules had to wait many years for the development of sufficiently sensitive techniques, and the structure of one of them, Ecteinascidin 743, was determined by KL Rinehart at the University of Illinois in 1984.[2] Rinehart had collected his sea squirts by scuba diving in the reefs of the West Indies.[3] Recently, the biosynthetic pathway responsible for producing the drug, as well as the bacterial symbiont of the tunicate responsible for production have been reported.[4]
The Spanish company PharmaMar licensed the compound from the University of Illinois before 1994

[citation needed]

and attempted to farm the sea squirt with limited success.

[3]

Yields from the sea squirt are extremely low – it takes 1 tonne of animals to isolate 1 gram of trabectedin – and about 5 grams were believed to be needed for a clinical trial

[5]

so Rinehart asked the Harvard chemist E. J. Corey to search for a synthetic method of preparation. His group developed such a method and published it in 1996.

[6]

This was later followed by a simpler and more tractable method which was patented by Harvard and subsequently licensed to PharmaMar.

[3]

The current supply is based on a semisynthetic process developed by PharmaMar starting from Safracin B, an antibiotic obtained by fermentation of the bacterium Pseudomonas fluorescens.

[7]

PharmaMar have entered into an agreement with Johnson and Johnson to market the compound outside Europe.[citation needed]

Trabectedin was first dosed in humans in 1996.[citation needed] In 2007, the EMEA gave authorisation for the marketing of trabectedin, under the trade name Yondelis, for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. The agency’s evaluating committee, the CHMP observed that trabectedin had not been evaluated in an adequately designed and analyzed randomized trial against current best care, and that the clinical efficacy data was mainly based on patients with liposarcoma and leiomyosarcoma. However the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease the CHMP considered that marketing authorisation could be granted under exceptional circumstances.[8] As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomal translocations could be used to predict responsiveness to trabectedin.[9] Trabectedin is also approved in South Korea[10] and Russia.

In 2008 the submission was announced of a registration dossier to the European Medicines Agency (EMEA) and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer. In 2011, Johnson&Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional Phase III study to be done in support of the submission.[11]

Trabectedin is also in phase II trials for prostate, breast and paediatric cancers.[12]

[edit] Structure

Trabectedin is composed of 3 tetrahydroisoquinoline moieties, 8 rings including one 10-membered heteocyclic ring containing a cysteine residue, and 7 chiral centers.

[edit] Synthesis

The biosynthesis of trabectedin is believed to involve the dimerization of two tyrosine residues to form the pentacyclic core of the molecule. The total synthesis by E.J. Corey used this proposed biosynthesis to guide their synthetic strategy. The synthesis uses such reactions as the Mannich reaction, Pictet-Spengler reaction, the Curtius rearrangement, and chiral rhodium-based diphosphine-catalyzed enantioselective hydrogenation. A separate synthetic process also involved the Ugi reaction to assist in the formation of the pentacyclic core. This reaction was unprecedented for using such a one pot multi-component reaction in the synthesis of such a complex molecule.

[edit] Mechanism of action

The biological mechanism of action is believed to involve the production of superoxide near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis. The actual mechanism is not yet known, but is believed to proceed from reduction of molecular oxygen into superoxide via an unusual auto-redox reaction on a hydroxyquinone moiety of the compound following. There is also some speculation the compound becomes ‘activated’ into its reactive oxazolidine form.

 

Editor’s note:  This following (inserted study in green font) could not demonstrate that N-acetylcysteine interacts with Superoxide which is hypothesized to be an important part of Trabectedin’s anti-tumor action: “no reaction of N-acetylcysteine with superoxide (O2-) could be detected within the limits of our assay procedures.”
The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid.
(PMID:2546864)
Department of Biochemistry, University of London King’s College Strand Campus, U.K.
Type:  Journal Article, Research Support, Non-U.S. Gov’t
DOI: 10.1016/0891-5849(89)90066-X
Aruoma OI, Halliwell B, Hoey BM, Butler J
N-acetylcysteine has been widely used as an antioxidant in vivo and in vitro. Its reaction with four oxidant species has therefore been examined. N-acetylcysteine is a powerful scavenger of hypochlorous acid (H–OCl); low concentrations are able to protect alpha 1-antiproteinase against inactivation by HOCl. N-acetylcysteine also reacts with hydroxyl radical with a rate constant of 1.36 X 10(10) M-1s-1, as determined by pulse radiolysis. It also reacts slowly with H2O2, but no reaction of N-acetylcysteine with superoxide (O2-) could be detected within the limits of our assay procedures.

 

 

[edit] References

  1. ^ Lichter et al.. Worthen LW. ed. Food-drugs from the sea. Proc: Aug 20–23, 1972.. 173. Marine Tech Soc. pp. 117–127.
  2. ^ Rinehart KL (January 2000). “Antitumor compounds from tunicates”. Med Res Rev 20 (1): 1–27. doi:10.1002/(SICI)1098-1128(200001)20:1<1::AID-MED1>3.0.CO;2-A. PMID 10608919.
  3. ^ a b c “Potent cancer drugs made — Sea squirts provide recipe”.
  4. ^ Rath CM et al (November 2011). “Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743″. ACS Chem Bio 6 (11): 1244–56. PMID 21875091.
  5. ^ “New Scientist”.
  6. ^ E. J. Corey, David Y. Gin, and Robert S. Kania (1996). “Enantioselective Total Synthesis of Ecteinascidin 743″. J. Am. Chem. Soc. 118 (38): 9202–9203. doi:10.1021/ja962480t.
  7. ^ C. Cuevas et al. (2000). “Synthesis of ecteinascidin ET-743 and phthalascidin PT-650 from cyanosafracin”. B. Org. Lett. 2: 2545–2548.
  8. ^ “CHMP evaluation”.
  9. ^ “PharmaMar website”.
  10. ^ S.Korea approves Zeltia cancer drug Yondelis, Reuters.com, May 8, 2008
  11. ^ Grogan, Kevin (3 May 2011). “J&J pulls submission for Zeltia’s Yondelis”. PharmaTimes Magazine (London, England): Online PharmaTimes. Archived from the original on 7 May 2011. Retrieved 7 May 2011.
  12. ^ “PharmaMar website”.

[show]

ET-743 (Yondelis): A Novel Agent with Activity in Soft Tissue Sarcomas

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Posted 15 Mar 2012 — by James Street
Category Combination Treatments, Drug Interactions, Drug Resistance, Osteosarcoma, Sarcoma, Trabectedin, Yondelis
  1. Jérôme Fayettea,b,
  2. Isabelle Ray Coquarda,
  3. Laurent Albertia,
  4. Dominique Ranchèrea,
  5. Helen Boylea and
  6. Jean-Yves Blaya,b

+ Author Affiliations


  1. aHôpital Edouard Herriot, Medical Oncology Department, Lyon, France;

  2. bINSERM U590, Centre Léon Bérard, Lyon, France
  1. Jean-Yves Blay, M.D., Ph.D., Hôpital Edouard Herriot, Service d’oncologie médicale, Pavillon E, 5 place d’Arsonval, 69003 LYON, France. Telephone: 33-4-72-11-73-98; Fax: 33-4-72-11-73-28; e-mail: blay@lyon.fnclcc.fr
  • Received September 19, 2005.
  • Accepted September 26, 2005.

Learning Objectives

After completing this course, the reader will be able to:

  1. Describe the original mechanism of action of ET-743.

  2. Explain the management of patients treated with ET-743, including what biological exams are needed because of toxicity and what is the optimal schedule of administration.

  3. Choose the best histological subtype of sarcoma for treatment with ET-743 and describe the clinical aim of treatment.

  4. Discuss putative combinations of ET-743 with other therapies.

Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com

Abstract

Ecteinascidin-743 (ET-743) is a natural product derived from the marine tunicate Ectenascidia turbinate. ET-743 binds in the minor groove of DNA, blocks transcription factors activity, and traps protein from the nucleotide excision repair system, thus blocking cells in G2-M phase. ET-743 demonstrated cytotoxic activity at very low concentrations against sarcoma cell lines in pre-clinical studies. In several phase II clinical studies in patients with advanced sarcoma failing conventional doxorubicin- and ifosfamide-based chemotherapy, ET-743 delivered by continuous intravenous 24-hour infusion at a dose of 1,500 μg/m2 every 21 days yielded 8% overall response and 30%–40% stabilization rates for a clinical benefit rate close to 40%. Interestingly, long-term stabilizations over more than 3 years have been described. In vivo, ET-743 has a specific toxicity profile, the major toxicity of this product being hepatic, through biliary duct destruction, and hematologic. ET-743 has also been evaluated in first-line treatment for these patients. Finally, due to its original mode of action and the lack of cross-resistance with other chemotherapy agents, ET-743 was tested in a preclinical model in combination with other drugs. Synergy was reported in vitro with doxorubicin and cisplatin; phase I combination studies are in progress.

Introduction

Despite an optimal loco-regional treatment, 35%–50% of patients with sarcoma will develop metastasis. Systemic chemotherapy is then the standard treatment; the active drugs are doxorubicin and ifosfamide and, to a lesser extent, dacarbazine [1, 2]. Initial response rates to doxorubicin-containing regimens are close to 10%–30%, with few long-term survivors. In second line, after failure of doxorubicin and ifosfamide, no drug had demonstrated significant antitumor activity so far. Ecteinascidin-743 (ET-743) is a tetrahydro-isoquinoline alkaloid isolated from Ectenascidia turbinata, a tunicate that grows on mangrove roots throughout the Caribbean Sea. At nanomolar concentrations, ET-743 is active against a variety of solid tumor cell lines, including sarcoma cell lines. In this review, we will describe the mechanism of action of ET-743, its toxicity, its clinical results in sarcomas, and its future development, including new associations.

Mechanism of Action

ET-743 binds in the minor groove of DNA and alkylates N2 of guanines located either in the 5′-PuGC-3′ or 5′ PyrGG-3′ sequence [3], which bends DNA toward the major groove [4]. Other alkylations are formed, but they are reversible and less stable [4]. Two of the three subunits of the drug bind to DNA while the third does not have contact with DNA and protrudes out from the minor groove, interfering with several DNA-binding factors. ET-743 strongly inhibits the binding of NF-Y [5], a factor that activates the CCAAT element present in 25% of eukaryotic promoters, including many promoters that regulate genes controlling the cell cycle. In vivo studies showed that the HSP70 promoter containing two CCAAT boxes activated by NF-Y is rapidly inhibited by ET-743 whereas other promoters lacking CCAAT boxes were not affected [6]. Importantly, the MDR1 (multidrug resistance) gene encoding for the P glycoprotein (P-gp) is also under dependence of a promoter containing CCAAT boxes [7]. This may explain why ET-743 is efficient against cells over-expressing MDR1 and why it does not select for the emergence of a P-gp phenotype in ET-743–resistant cell lines or exhibit cross-resistance with other cytotoxic agents [8]. Actually, ET-743 is a general inhibitor of cancer-activated transcription but not of “uninduced” (i.e., basal) transcription: Induction of the Sp1-regulated p21 gene by Trichostatin A (TSA), a promoter activator, was blocked by ET-743 at concentrations that had minimal effect on uninduced constitutive expression, and microarray analysis of cells treated with TSA and/or ET-743 indicated that activation of TSA-responsive promoters was blocked by ET-743 with little effect on nonresponsive promoters [9]. In addition, ET-743 at higher concentrations can alter the interaction between several DNA-binding proteins and DNA. (Two subunits of NF-Y exhibit homology with histones 2A and 2B.) ET-743 may target topoisomerase I, resulting in DNA breaks [10], although this may not be relevant in vivo because this effect is observed at high concentration and the drug remains active in cells deficient for topoisomerase I [11, 12].

ET-743 activity may also involve the DNA repair machinery. Defects in the mismatch repair pathway, usually associated with increased resistance to methylating agents and cisplatin, do not affect the cytotoxic activity of ET-743 [11]. DNA-dependent protein kinase may repair ET-743–induced damages because it is active in cells deficient in this enzyme [11]. Whereas all known DNA-interacting cytotoxic drugs are either more or equally active in nucleotide excision repair (NER)–deficient cells, ET-743 exerts decreased cytotoxic activity in NER-deficient cell lines [11, 13, 14]. Indeed, ET-743 interacts with the transcription-coupled NER machinery to induce lethal DNA strand breaks. The preferred binding sequences for ET-743 are less efficiently excised and trap DNA-NER proteins, forming cytotoxic complexes similar to a poisoned topoisomerase I- or topoisomerase II-DNA complex. In the absence of an intact NER nuclease complex, this toxic lesion does not occur, and the ET-743–DNA adducts, though not repaired by the NER pathway, are less toxic to cells [15]. Moreover, translesion synthesis and homologous recombinations lead to ET-743 resistance of NER-deficient cells [16]. p53 may activate apoptosis after ET-743–induced DNA damage because an increase of p53 is observed in cell lines expressing wild-type p53. However, p53 status does not appear to correlate to sensitivity to ET-743 [17]. Finally, the telomerase activity decreases the efficiency of ET-743, [18].

ET-743 blocks cells in G2-M phase. Indeed, cell lines exposed to ET-743 for 1 hour progress through S phase more slowly than control cells and then accumulate in the G2-M phase. The sensitivity to ET-743 of G1 synchronized cells was much higher than that of cells synchronized in S phase and even higher than that of cells synchronized in G2-M [13, 17]. Expression microarray experiments were used to identify genes involved in sensitivity or resistance to ET-743. A first study determined a set of 70 genes whose expression was modulated in drug-resistant cells [19]. Another study with a cDNA microarray containing 6,700 cancer-related genes showed upregulation of 86 genes and downregulation of 244 genes in response to ET-743 [20]. Immunochemistry revealed marked differences in the cytoskeleton architecture between ET-743–sensitive and –resistant cells, and collagen I seems to be an important protein [21].

ET-743, then, exerts its cytotoxic role through an original mode of action involving DNA repair machinery. Its potent cytotoxic activity on sarcoma cell lines prompted investigation of its activity in the clinic.

Toxicity in Clinical Trials

The most prominent toxicities observed in the different phase II studies were grade 3 or 4 transaminase increase (26%–59%, [22–26]) and neutropenia (33%–52%, [22–26]). Regarding liver toxicity, studies in rats showed a predominant biliary toxicity: Twenty-four hours after ET-743, liver degeneration and patchy focal necrosis of bile duct epithelial cells were observed and associated with mild inflammation followed by fibrosis.

Sporadic and focal zones of hepatic necrosis and hemorrhage were observed although the majority of hepatocytes appeared normal. Pathological alterations persisted up to 3 months [27]. In humans, patients with any baseline liver-function test exceeding the upper limit of the normal ranges have a significantly greater incidence of severe hepatic toxicity [28]. Levels of plasma liver enzymes (e.g., transaminases, bilirubin, alkalin phosphatases, and 5′-nucleotidase) should be checked before each course. Dexamethasone may decrease this toxicity [28]. Pretreatment, but not concomitant treatment, of rats with high dose of dexamethasone 24 hours before ET-743 improved or prevented ET-743–induced liver damages [29], probably through the induction of the cytochrome p450. Beta-naphthoflavone [30] and indole-3-carbinol [31] may protect liver as well. Granulocytic (colony-forming units granulocyte-macrophage [CFU-GM]) and megakaryocytic progenitors are sensitive to the drug [32], but the dose of ET-743 that inhibits 90% of CFU-GM only inhibited 45% survival of stem cells, resulting in the lack of long-term myelosuppression [33]. A specific toxicity for monocytes/macrophages may account for the anti-inflammatory properties of ET-743 [34].

ET-743 as Monotheraphy in Patients with Sarcoma

Different preclinical and phase I studies determined the schedule of administration: The recommended schedule for ET-743 is delivered by continuous intravenous 24-hour infusion at the dose of 1,500 μg/m2 every 3 weeks, until progression or toxicity. Table 1⇓ gives a synthetic overview of the management of ET-743 in sarcoma.

Table 1.

Summary for ecteinascidin-743 (ET-743) use

A first multicentric phase II study enrolled 54 heavily pretreated patients. Before ET-743, 48% had received one or two drugs and 52% three or more; 41% had leiomyosarcoma (eight of 22 of uterine origin). Two partial responses (PRs) were observed, for an overall response (OR) rate of 4% (95% confidence interval [CI], 0.5%–12.8%). Four minor responses and nine disease stabilizations (SDs) lasting more than 6 months were observed. Twenty-four percent of patients were free from progression at 6 months. The median survival was 12.8 months, with 30% of patients alive at 2 years. Two treatment-related deaths occurred [35].

The second study included 36 patients and reported one complete response (CR) and two PRs for a response rate of 8% (95% CI, 2%–23%), with a clinical benefit of 14%. Prolonged responses were observed (up to 20 months), and the 1-year overall survival was 53% (95% CI, 39%–73%), an unusual observation in this population of patients [22].

These results were confirmed by a large phase II study of the Soft Tissue and Bone Sarcoma Group of the European Organization for Research and Treatment of Cancer in 104 pretreated patients. Eight PRs were observed for an OR rate of 8%, and 45 SDs (longer than 6 months in 26% patients) were observed. A clinical benefit was observed for 56% of leiomyosarcoma and 61% of synovialosarcoma patients. The progression-free survival at 6 months was 29% [24]. The median duration of survival of 9.2 months was again unusually high in this cohort of heavily pretreated patients, especially considering the low response rate. The rates of objective regression and stable disease are similar in doxorubicin/ifosfamide chemosensitive and chemoresistant sarcomas. However, in this study, patients exhibiting a prolonged stable disease had an outcome similar to responding patients, supporting the relevance of the progression arrest rate (i.e., objective response + stable disease) as a prognostic parameter instead of objective response [36].

In a single institution experience, 89 patients (82 assessable) with advanced refractory sarcoma (leiomyosarcoma 36%, liposarcoma 18%, and osteosarcoma 16%) were treated with ET-743. The objective response rate was 7% (one CR, five PRs), and the clinical benefit rate at 3 and 6 months was 38% and 23%, respectively [26].

To decrease toxicity, a randomized phase II study of ET-743 given by two different dosing schedules (3-hour infusion weekly × 3 every 4 weeks versus 24-hour infusion every 3 weeks) in patients with leiomyosarcoma or liposarcoma (due to the observed better activity of ET-743 in these subtypes with respect to the other) refractory to conventional doxorubicin and ifosfamide chemotherapy was carried out. Objective responses and stable disease were observed in a subset of refractory patients with both treatment schedules, but response rate and progression-free survival were superior with 24-hour CIV (continuous infusion of vancomycin) treatment [37]. This trial has been extended, and final results are expected at the end of 2005. A comparative phase III trial of ET-743 and ifosfamide is under discussion in patients with an anthracycline-refractory uterine leiomyosarcoma.

After promising results in pretreated patients, ET-743 was tested in the first line of treatment of unresectable advanced sarcoma. Thirty-six patients (35 assessable) were treated with the standard schedule: One CR and five PRs were achieved for an OR rate of 17.1% (95% CI, 6.6%–33.6%). In addition, one patient had a minor response. The estimated 1-year progression-free and overall survival rates were 21% (95% CI, 11%–41%) and 72% (95% CI, 59%–88%), respectively [25]. ET-743 was ineffective in gastrointestinal stromal tumor [23] and in osteosarcoma [38], but responses were reported in Ewing sarcoma [39].

ET-743 in Combination with Other Drugs

Because of its original mechanism of action, ET-743 may act synergistically in combination with other cytotoxic agents. Several preclinical or phase I studies explored this possibility. Preclinical studies showed that ET-743 and cisplatin are synergic, without additive toxicity [40]. Interestingly, ET-743 could be used at lower, relatively nontoxic doses to potentiate cytotoxicity of cisplatin. A phase I study was performed to determine ET-743 and cisplatin doses in combination regimens [41]. The combination with doxorubicin may be effective for tumors displaying low sensitivity to each drug given alone [42]. For tumor cells sensitive to both agents, additive effects are observed, whereas another study showed synergy [43]. The most favorable synergy in vitro was observed using a sequence with ET-743 first, followed by doxorubicin. Based on these findings, phase I studies on the combination of both drugs were initiated. Other combinations were tested with paclitaxel (showing a limited schedule dependent synergy) and with plasminogen-related protein B (an antiangiogenic factor) in preclinical models of chondrosarcoma [44]. No synergy was observed, however, between ET-743 and radiotherapy [45].

Conclusion

ET-743 has an original mode of action, involving enzymes of the DNA repair machinery. ET-743 has a demonstrated activity as first or second treatment of advanced sarcomas, after doxorubicin, ifosfamide, and dacarbazine. Some patients achieved very prolonged long-term survival. The utility of combination regimens, as well as the activity of this agent in other tumor types, in particular ovarian carcinoma, is currently under investigation.

Disclosure of Potential Conflicts of Interest

The authors indicate no potential conflicts of interest.

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Anti-inflammatory Properties of the Novel Antitumor Agent Yondelis (Trabectedin): Inhibition of Macrophage Differentiation and Cytokine Production

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Posted 15 Mar 2012 — by James Street
Category Osteosarcoma, Sarcoma, Trabectedin, Yondelis
  1. Paola Allavena1,
  2. Mauro Signorelli1,3,
  3. Marcello Chieppa1,
  4. Eugenio Erba2,
  5. Giancarlo Bianchi1,
  6. Federica Marchesi1,
  7. Chiara Omero Olimpio1,
  8. Claudia Bonardi3,
  9. Annalisa Garbi3,
  10. Andrea Lissoni3,
  11. Filippo de Braud4,
  12. José Jimeno6, and
  13. Maurizio D’Incalci2,5

+ Author Affiliations


  1. Departments of 1Immunology and Cell Biology and 2Oncology, “Mario Negri” Institute; 3Department of Obstetrics and Gynecology, University of Milano Bicocca, Hospital S. Gerardo; 4START Project, European Institute of Oncology; 5Southern Europe New Drugs Organization, Milan, Italy; and 6Pharmamar, Madrid, Spain
  1. Requests for reprints:
    Paola Allavena, Istituto Ricerche Farmacolgiche Mario Negri, Via Eritrea 62, 20152 Milano, Italy. Phone: 39-02-390141; Fax: 39-02-39014596; E-mail: allavena@marionegri.it.

Abstract

Yondelis (Trabectedin) is a novel antitumor agent of marine origin extracted from the tunicate Ecteinascidia turbinata. This original compound is active against several human tumors including sarcoma and ovarian and breast adenocarcinoma, as evidenced in phase II clinical trials in advanced multitreated patients. Yondelis is a DNA minor groove binder that blocks cell cycle and interferes with inducible gene transcription in a selective manner. In this study, we investigated the immunomodulatory properties of Yondelis on leukocytes. Human blood monocytes were highly susceptible in vitro to its cytotoxic effect and underwent apoptosis at pharmacologically relevant concentrations (5 nmol/L), whereas lymphocytes were up to 5-fold less sensitive. Macrophages differentiated in vitro with macrophage colony-stimulating factor and tumor-associated macrophages (TAM), isolated from patients with ovarian cancer, were also susceptible. At subcytotoxic concentrations, Yondelis inhibited the in vitro differentiation of monocytes to macrophages. In tumor-treated patients, drug infusion caused a selective decrease of monocyte counts and of ex vivo macrophage differentiation. The in vitro production of two proinflammatory mediators, CCL2 and IL-6, was markedly reduced by Yondelis in monocytes, macrophages, TAM, and freshly isolated ovarian tumor cells. The chemokine CCL2 is the major determinant of monocyte recruitment at tumor sites, whereas IL-6 is a growth factor for ovarian tumors. In view of the protumor activity of TAM and of the strong association between chronic inflammation and cancer progression, the inhibitory effect of Yondelis on macrophage viability, differentiation, and cytokine production is likely to contribute to the antitumor activity of this agent in inflammation-associated human tumors.

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