Archive for the ‘Molecular’ Category

blocking a molecule called M-CSF, suppressed osteosarcoma tumor growth even after treatment was stopped

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Posted 13 Aug 2010 — by James Street
Category Molecular, Molecular Osteosarcoma Studies, Prostate Cancer

On the heels of dismaying reports that a promising antitumor drug could, in theory, shorten patients’ long-term survival, comes a promising study by a Japanese team of researchers that suggests a potentially better option. The study appears in the May 11 issue of the Journal of Experimental Medicine (online April 27). Many cancer treatments work by disrupting the formation of new blood vessels that feed growing tumors. Agents that block a vessel-promoting factor called VEGF have shown promise in human clinical trials. But recent studies in mice show that when treatment stops, tumor growth rapidly resumes. Now, Yoshiaki Kubota and colleagues find that blocking a different molecule, called M-CSF, suppressed tumor growth even after treatment was stopped.

Kubota and his team compared the efficacy of inhibitors against M-CSF and VEGF in mice with a certain kind of bone tumor. Three weeks of anti-VEGF treatment suppressed tumor growth but, similar to other recent reports, the tumors bounced back when the drug treatment was curtailed. Tumor growth in mice on a similar regiment of an M-CSF inhibitor remained suppressed in the absence of drug.

Another distinction between the two inhibitors was the type of vessel growth that was blocked. Blocking VEGF prevented dangerous vessels from growing such as those that feed tumors. But it also stopped beneficial vessels from growing, such as those that help injured tissues heal. Blocking M-CSF, on the other hand, only impeded bad vessel growth.

Most likely, the anti–M-CSF treatment had a lasting effect because it resulted in damage to the scaffolding that surrounds cancerous vessels, robbing the tumors of the structural support they need to grow. Meanwhile, the scaffold of mice treated with anti-VEGF remained intact.

M-CSF levels soar in patients with osteosarcoma (a malignant bone cancer), breast cancer and prostate cancer, making these cancers potentially the most responsive to M-CSF-blocking drugs Whether or not other types of cancer rely more on M-CSF than on VEGF for their blood supply remains unknown.

First Diagnostic Test to Predict Prostate Cancer Recurrence

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Posted 13 Aug 2010 — by James Street
Category Diagnostic, Individualized treatment, Molecular, Prostate Cancer, genetic research

Myriad Genetics Launches PROLARIS(TM): First Diagnostic Test to Predict Prostate Cancer Recurrence
Globe Newswire
March 02, 2010: 08:36 AM ET

SALT LAKE CITY, March 2, 2010 (GLOBE NEWSWIRE) — Myriad Genetics, Inc. (Nasdaq:MYGN) today announced the launch of PROLARIS™, a 46-gene prognostic test which quantitatively determines the risk of recurrence in patients who have undergone prostatectomy surgery.

For the first time, physicians now have a direct molecular measure of a prostate tumor’s capacity to divide and grow by examining the mechanics of growth at the molecular level. PROLARIS is the Company’s eighth molecular diagnostic product and the first of two that are planned to be launched this year.

“After undergoing a radical prostatectomy, men often worry about their continuing risk of cancer recurrence,” said Peter R. Carroll, M.D., M.P.H., Professor and Chair, Urology, University of California, San Francisco. “PROLARIS may offer very important information to the patient and his physician about the risk of his cancer recurring.”

PROLARIS is a molecular diagnostic assay that offers urologists a more accurate way of determining a prostate cancer patient’s risk of recurrence. The new molecular diagnostic test is based on cell growth and tumor biology and provides rigorous, quantitative measures of the expression levels of multiple genes related to progression of the cell cycle.

The test identifies patients at low risk of disease recurrence with 95% certainty giving these men confidence that additional aggressive treatment with the accompanying toxicity and adverse events is likely unwarranted. Conversely, men with high PROLARIS scores would be considered for more intensive screening and adjuvant therapy to address their more aggressive disease.

The Company is performing additional clinical validation studies to expand the utility of PROLARIS. In one such recently completed study of 365 prostate cancer patients, 98.5% of prostate cancer patients with a low (favorable) PROLARIS score survived their disease after 10 years, compared to 57.6% of the patients receiving a high (unfavorable) score who died of prostate cancer within 10 years.

“PROLARIS is a valuable additional tool that will enable urologists to provide an accurate, individualized recurrence risk score to men who have undergone a radical prostatectomy,” stated Mark C. Capone, President, Myriad Genetic Laboratories, Inc. “We view PROLARIS as the first of a strong emerging stable of RNA signature tools based on fundamental tumor biology which Myriad will offer to the urology/oncology community.”

In the United States, 192,000 men are diagnosed with prostate cancer each year and 80,000 men will undergo a radical prostatectomy, a surgical procedure that removes the prostate gland and some surrounding tissue. Approximately 35% of these men will eventually have a biochemical recurrence indicating the return of their prostate cancer. Current models based on clinical variables cannot effectively predict in which of these men the disease will recur.

Myriad will introduce PROLARIS to urologists and oncologists through its established oncology sales force and new urology sales team in the coming weeks. The cost for PROLARIS is $3,400.

Clinical Data on PROLARIS to be Presented

The clinical validation and scientific data supporting PROLARIS will be presented at the 2010 Genitourinary Cancers Symposium on March 5-7, 2010 in San Francisco. The abstract of the presentation entitled: “Cell Cycle Genes Predict Recurrence After Radical Prostatectomy” by Dr. Gregory P. Swanson and colleagues will be publically released on  the American Society of Clinical Oncology’s website, www.asco.org on Wednesday, March 3, 2010 at 6:00 pm Eastern.

About Myriad Genetics

Myriad Genetics, Inc. is a leading molecular diagnostic company focused on developing and marketing novel predictive medicine, personalized medicine and prognostic medicine products. Myriad’s news and other information are available on the Company’s Web site at www.myriad.com.

Myriad, the Myriad logo, BRACAnalysis, Colaris, Colaris AP, Melaris, TheraGuide, Prezeon, OnDose, and Prolaris are trademarks or registered trademarks of Myriad Genetics, Inc. in the United States and foreign countries. MYGN-G

The Myriad Genetics, Inc. logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=6336

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the timing and manner of the launch and introduction of PROLARIS to urologists and oncologists; the planned launch of a second molecular diagnostic product this year; the degree of certainty in identifying patients at low or high risk of disease recurrence with PROLARIS; the consideration or role of the PROLARIS score or results in subsequent medical management decisions; the timing, completion and results of additional clinical validation studies to expand the utility of PROLARIS; the value and utility of PROLARIS to provide accurate individualized recurrence risk scores to men who have undergone radical prostatectomy; the Company’s anticipated offering of a strong emerging stable of RNA signature tools based on fundamental tumor biology; the initial cost for PROLARIS of $3,400; and the presentation of clinical data on PROLARIS at the 2010 Genitourinary Cancers Symposium on March 5-7, 2010 in San Francisco. These “forward-looking statements” are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by forward-looking statements. These risks and uncertainties include, but are not limited to: the risk that sales and profit margins of our existing molecular diagnostic products may decline or will not continue to increase at historical rates; the risk that we may be unable to develop or achieve commercial success for additional molecular diagnostic products in a timely manner, or at all; the risk that licenses to the technology underlying our molecular diagnostic products and any future products are terminated or cannot be maintained on satisfactory terms; risks related to delays or other problems with manufacturing our products or operating our laboratory testing facilities; risks related to public concern over our products; risks related to regulatory requirements or enforcement in the United States and foreign countries and changes in the structure of healthcare payment systems; uncertainties about our ability to obtain new corporate collaborations and acquire new technologies on satisfactory terms, if at all; the development of competing products and services; the risk that we or our licensors may be unable to protect the proprietary technologies underlying our products; the risk of patent-infringement claims or challenges of our patents; risks of new, changing and competitive technologies and regulations in the United States and internationally; and other factors discussed under the heading “Risk Factors” contained in Item 1A in our Annual Report on Form 10-K for the year ended June 30, 2009,which has been filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. All information in this press release is as of the date of the release, and Myriad undertakes no duty to update this information unless required by law.

CONTACT:  Myriad Genetics, Inc.
Suzanne Barton, Director, Investor Relations
(801) 584-1138
sbarton@myriad.com

All-trans retinoic acid and interferon-alpha in the treatment of a patient with resistant metastatic osteosarcoma

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Posted 12 Aug 2010 — by James Street
Category Metastases, Molecular, Natural Therapies, Nutrition and Cancer

All-trans retinoic acid and interferon-alpha in the treatment of a patient with resistant metastatic osteosarcoma.

Todesco A, Carli M, Iacona I, Frascella E, Ninfo V, Rosolen A.

Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Universita di Padova, Padova, Italy.

BACKGROUND: A boy age 14 years who was in complete remission from Stage IIB small cell osteosarcoma, which was misdiagnosed as Ewing sarcoma and consequently was treated, developed inoperable lung metastases when he was off therapy.

He received second-line treatment for recurrent Ewing sarcoma, including chemotherapy and radiotherapy, and obtained only a temporary response.

A compassionate treatment with all-trans retinoic acid (ATRA) and interferon-alpha (IFNalpha) was then undertaken.

METHODS: The patient initially was treated according to the national SE91 protocol for nonmetastatic Ewing sarcoma. After a bilateral pulmonary recurrence, he received second-line chemotherapy and irradiation of the largest metastasis, with a temporary partial response.

The patient was then treated with a combination of oral ATRA (All-trans retinoic acid
) (90 mg/m(2) for 3 days per week) and subcutaneous IFNalpha (3 x 10(6) U/m(2) 5 days per week) for 4 months.

The same therapy also was administered for the control of residual disease after surgery for a total duration of 1 year of ATRA/IFN treatment. During the first 3 weeks of therapy, ATRA pharmacokinetics were studied.

RESULTS:

After progression of the patient’s disease, despite the administration of first-line and second-line chemotherapy, combined treatment with ATRA/IFNalpha yielded a partial remission, which allowed surgical resection of the largest metastasis.

The same therapy was effective in preventing tumor recurrence after incomplete removal of the remaining metastases.

Treatment was well tolerated, and the patient is in stable complete remission 14 months after the end of therapy.

The pharmacokinetics results confirmed the indication of an intermittent schedule for oral ATRA therapy.

CONCLUSIONS:

ATRA/IFNalpha treatment may be considered as an alternative approach in the treatment of patients with metastatic osteosarcoma who have disease that is resistant to conventional chemotherapy and in the treatment of patients with minimal tumor residue.

Copyright 2000 American Cancer Society.

Induction of cell death of human osteogenic sarcoma cells by zoledronic acid resembles anoikis

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Posted 11 Aug 2010 — by James Street
Category Chemotherapy, Molecular, Molecular Osteosarcoma Studies

Bone. 2003 Aug;33(2):216-28.

Evdokiou A, Labrinidis A, Bouralexis S, Hay S, Findlay DM.

Department of Orthopaedics and Trauma, University of Adelaide, Bice Building Level 4, The Royal Adelaide Hospital, North Terrace, Adelaide 5000, South Australia, Australia. andreas.evdokiou@adelaide.edu.au

The aim of this study was to investigate the cytotoxic activity of the third-generation nitrogen-containing bisphosphonate zoledronic acid (ZOL) as a single agent, and in combination with clinically relevant anticancer drugs, in a panel of human osteogenic sarcoma cell lines (HOS, BTK-143, MG-63, SJSA-1, G-292, and SAOS2).

We found that ZOL, when used alone, reduced cell number in a dose- and time-dependent manner, due either to cell cycle arrest in S-phase or to the induction of apoptosis.

In the sensitive HOS, BTK-143, and G-292 cell lines, genomic DNA fragmentation and morphological changes characteristic of apoptosis were evident, and cells became nonadherent.

Induction of apoptosis in osteosarcoma cells by ZOL was associated with caspase activation. However, coaddition of the broad-spectrum caspase inhibitors, z-VAD-fmk, Boc-D-fmk, or the caspase-3-specific inhibitor z-DEVD fmk, failed to protect these cells from ZOL-induced apoptosis.

Our data support a ZOL-specific induction of cell apoptosis that involves cell detachment (anoikis), and in which caspase activation occurs secondarily to, and is redundant as a mediator of cell death.

The addition of geranylgeraniol, an intermediate of the mevalonate pathway, suppressed the ZOL-induced apoptosis, suggesting that the cytotoxic effects of ZOL in osteosarcoma cells were mediated by the mevalonate pathway.

While treatment of osteosarcoma cells with the chemotherapeutic agents doxorubicin or etoposide decreased cell viability, combination of these agents with ZOL did not significantly augment apoptosis in any of the cell lines tested.

These observations suggest that ZOL has direct effects on the proliferation and survival of osteosarcoma cells in vitro, which has implications for future therapy of osteosarcoma.

PMID: 14499355 [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances
Publication Types:

* Research Support, Non-U.S. Gov’t

Concomitant tumour resistance in patients with osteosarcoma. A clue to a new therapeutic strategy

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Posted 11 Aug 2010 — by James Street
Category Molecular, Molecular Osteosarcoma Studies, Osteosarcoma Treatment Centers

J Bone Joint Surg Br. 2004 Jan;86(1):143-7.

Kaya M, Wada T, Nagoya S, Kawaguchi S, Isu K, Yamashita T.

Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan.

Abstract

Concomitant tumour resistance (CTR) is a unique phenomenon in which animals harbouring large primary tumours are resistant to the growth of smaller metastatic tumours by systemic angiogenic suppression.

To examine this clinically, in ten patients with osteosarcoma, we investigated the effects of removal of the primary tumour on the development of pulmonary metastases, the systemic angiogenesis-inducing ability and the serum levels of several angiogenesis modulators.

We found that removal of the primary tumour significantly elevated systemic angiogenesis-inducing ability in five patients who had post-operative recurrence of the tumour.

Post-operative elevation of the angiogenesis-induced ability was suppressed by the addition of an angiogenic inhibitor, endostatin.

Also, primary removal of the tumour decreased the serum levels of vascular endothelial growth factor and endostatin.

These findings suggest, for the first time, the presence of CTR in patients with osteosarcoma for whom post-operative antiangiogenic therapy may be used to prevent the post-operative progression of micrometastases.

PMID: 14765882 [PubMed - indexed for MEDLINE] Free Article

Proteasome inhibition with bortezomib suppresses growth and induces apoptosis in osteosarcoma

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Posted 10 Aug 2010 — by James Street
Category Chemotherapy, Molecular, Mouse Osteosarcoma Studies, Osteosardoma Research

* Abstract

Int J Cancer. 2010 Jul 1;127(1):67-76.

Shapovalov Y, Benavidez D, Zuch D, Eliseev RA.

Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.

Abstract

Osteosarcomas are primary bone tumors of osteoblastic origin that mostly affect adolescent patients. These tumors are highly aggressive and metastatic.

Previous reports indicate that gain of function of a key osteoblastic differentiation factor, Runx2, leads to growth inhibition in osteosarcoma.

We have previously established that Runx2 transcriptionally regulates expression of a major proapoptotic factor, Bax.

Runx2 is regulated via proteasomal degradation, and proteasome inhibition has a stimulatory effect on Runx2.

In this study, we hypothesized that proteasome inhibition will induce Runx2 and Runx2-dependent Bax expression sensitizing osteosarcoma cells to apoptosis.

Our data showed that a proteasome inhibitor, bortezomib, increased Runx2 and Bax in osteosarcoma cells.

In vitro, bortezomib suppressed growth and induced apoptosis in osteosarcoma cells but not in nonmalignant osteoblasts.

Experiments involving intratibial tumor xenografts in nude mice demonstrated significant tumor regression in bortezomib-treated animals.

Immunohistochemical studies revealed that bortezomib inhibited cell proliferation and induced apoptosis in osteosarcoma xenografts.

These effects correlated with increased immunoreactivity for Runx2 and Bax. In summary, our results indicate that bortezomib suppresses growth and induces apoptosis in osteosarcoma in vitro and in vivo suggesting that proteasome inhibition may be effective as an adjuvant to current treatment regimens for these tumors.

Published 2009 UICC.

This article is a US Government work and, as such, is in the public domain in the United States of America.

PMID: 19894220 [PubMed - indexed for MEDLINE]

GE Launches Study To Improve Diagnosis Of Early Stage Colon Cancer

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Posted 28 Jul 2010 — by James Street
Category Colon Cancer, Individualized treatment, Molecular

23 Jul 2010

A team of scientists at GE Global Research, the technology development arm for the GE (NYSE: GE), has launched a study with Memorial Sloan-Kettering Cancer Center, (MSKCC) one of the world’s premier cancer centers, to better understand the early stages of colon cancer. The goal is to yield new insights that improve treatment selection and outcomes for cancer patients in the future.

“Information is one of the best weapons we have in the fight against cancer,” said John Burczak, Chief Scientist for Molecular Imaging at GE Global Research. “With colon cancer, we know that not all cases in the early stages of the disease are alike. Some are more aggressive than others. Through the promise of molecular analysis, we can identify those patients at higher risk and help ensure they receive the best possible treatment option.”

One of the primary issues in cancer diagnosis today is the limited amount of molecular information pathologists have about a particular cancer. At the time of diagnosis, little is determined about the characteristics of cancer itself such as how fast or slow it may be growing. New breakthroughs in molecular medicine are promising to change this paradigm.

Last October, GE scientists announced a major cancer research breakthrough in molecular pathology that is unlocking information about cancer previously hidden from view. This molecular information will not only increase our understanding of cancer; it could improve treatment selection for patients. This is particularly true for patients with early stage colon cancer.

Today, the standard treatment for early stage, or Stage 1 and Stage 2 colon cancer is surgery. However, the cancer recurrence rate for Stage 2 cases is high at approximately 25% because more aggressive forms of these cases go undetected.

New molecular analysis from cancer mapping tools such as GE’s have the potential to change this paradigm, so that these cases can be identified and directed to the appropriate treatment.

As part of the study, GE and MSKCC will collaborate to evaluate biomarkers for their prognostic value to segregate high from low risk early stage colon cancers. Scientists and investigators from GE and MSKCC will work together to first identify cancer cases, acquire and process cancer tissues, and collect treatment outcome information, then biochemically and statistically analyze the molecular profiles for the cancer tissues, and relate the molecular profiles to treatment outcomes.

GE’s Cancer Mapping Technology

GE scientists have developed new molecular pathology technology that can create a visual map of more than 25 proteins within a single tissue sample at the sub-cellular level and apply sophisticated imaging analysis tools to collect and interpret the data. With the ability to study multiple proteins in one sample, GE’s technology could provide more insight than ever before into the signaling networks and cell activity that may characterize different types of cancers.

Currently, a diagnosis of cancer and the decision of which therapy to prescribe are based on the histology of the tumor and, in some cases, the expression of just one or two biomarkers inside the patient’s tumor. To enable more biomarkers to be mapped and viewed together in one slide, GE researchers built a prototype system that can stain, wash and re-stain tissue samples for study under a digital microscope. The system combines image analysis of cancerous cells and structures with GE’s patented visualization tools to provide a color map of multiple protein concentrations within the sample. With the ability to visually map cancer in this way, GE is hopeful that critical information about the disease can be uncovered that was previously hidden from view.

The goal of GE’s protein mapping technology program is to provide new insights into cancer that one day will assist physicians to better determine the prognosis for a cancer and the appropriate treatment. These insights also may be useful in saving drug companies time and money in the development of new therapies. With more information, drug companies may be able to better understand what patients will and won’t respond and overall, help them make more informed choices during the development process.

GE’s research programs in protein mapping and molecular pathology are aligned with GE’s healthymagination initiative, which is built on the global commitments of reducing costs, improving quality and expanding access to healthcare for millions of people.

Source:
GE Global Research

Article URL: http://www.medicalnewstoday.com/articles/195579.php

Main News Category: Colorectal Cancer

Also Appears In:  Cancer / Oncology,