Defeat Osteosarcoma » Mouse Osteosarcoma Studies

Effect of combined COX-2 and matrix metalloproteinase inhibition on human sarcoma xenografts

James Street — Fri, 13 Aug 2010 05:57:21 +0000

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12972806

Dickens DS, Cripe TP.

Division of Pediatric Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Ohio 45229, USA.

PURPOSE:

Sarcomas express cyclooxygenase (COX)-2, an inducible enzyme with known tumor-promoting activity.

COX-2 inhibition is efficacious against many cancer types but has not been tested for human sarcomas.

Matrix metalloproteinase (MMP) inhibitors also possess antiproliferative activity.

Because MMP inhibitor therapy induces COX-2 expression, the authors hypothesized that the combination of COX-2 and MMP inhibitors results in a synergistic antitumor effect.

METHODS:

Human osteosarcoma or rhabdomyosarcoma cells were injected into athymic mice.

Tumor development and growth were measured following treatment with a COX-2 inhibitor (celecoxib), an MMP inhibitor (doxycycline), or both.

The tumors were analyzed for necrosis, apoptosis, cyclooxygenase activity (PGE2 production), and MMP-2 levels.

RESULTS:

When treatment was started prior to tumor cell implantation, doxycycline inhibited osteosarcoma tumor growth alone and in combination with celecoxib (30% and 33% reduction, respectively).

An effect on osteosarcoma tumor implantation rates was noted in mice receiving doxycycline alone and in combination with celecoxib (12.5% and 6.25% reduction, respectively).

Established osteosarcoma and rhabdomyosarcoma tumors were inhibited only by combination therapy (36% and 55%, respectively).

A higher proportion of osteosarcoma tumors in the combination therapy group had more than 50% necrosis (3/7) when compared with control tumors (0/8).

Antitumor effects did not correlate with PGE2 levels, suggesting the observed interaction with doxycycline was due to previously described non-enzymatic effects of celecoxib.

CONCLUSIONS:

The authors’ preclinical data suggest that the combination of inexpensive, nontoxic, oral COX-2 and MMP inhibitors may be useful for the treatment of some types of solid tumors.

The insulin-like growth factor-1 receptor-targeting antibody, CP-751,871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma.

James Street — Fri, 13 Aug 2010 05:51:18 +0000

Cancer Res. 2009 Oct 1;69(19):7662-71. Epub 2009 Sep 29.

Kurmasheva RT, Dudkin L, Billups C, Debelenko LV, Morton CL, Houghton PJ.

Departments of Molecular Pharmacology, Biostatistics, and Pathology, St. Jude Children’s Research Hospital, Memphis, TN38105, USA.

Abstract

Signaling through the type 1 insulin-like growth factor receptor (IGF-1R) occurs in many human cancers, including childhood sarcomas.

As a consequence, targeting the IGF-1R has become a focus for cancer drug development.

We examined the antitumor activity of CP-751,871, a human antibody that blocks IGF-1R ligand binding, alone and in combination with rapamycin against sarcoma cell lines in vitro and xenograft models in vivo.

In Ewing sarcoma (EWS) cell lines, CP751,871 inhibited growth poorly (<50%), but prevented rapamycin-induced hyperphosphorylation of AKT(Ser473) and induced greater than additive apoptosis.

Rapamycin treatment also increased secretion of IGF-1 resulting in phosphorylation of IGF-1R (Tyr1131) that was blocked by CP751,871.

In vivo CP-751,871, rapamycin, or the combination were evaluated against EWS, osteosarcoma, and rhabdomyosarcoma xenografts. CP751871 induced significant growth inhibition [EFS(T/C) >2] in four models.

Rapamycin induced significant growth inhibition [EFS(T/C) >2] in nine models.

Although neither agent given alone caused tumor regressions, in combination, these agents had greater than additive activity against 5 of 13 xenografts and induced complete remissions in one model each of rhabdomyosarcoma and EWS, and in three of four osteosarcoma models.

CP751,871 caused complete IGF-1R down-regulation, suppression of AKT phosphorylation, and dramatically suppressed tumor-derived vascular endothelial growth factor (VEGF) in some sarcoma xenografts.

Rapamycin treatment did not markedly suppress VEGF in tumors and synergized only in tumor lines where VEGF was dramatically inhibited by CP751,871.

These data suggest a model in which blockade of IGF-1R suppresses tumor-derived VEGF to a level where rapamycin can effectively suppress the response in vascular endothelial cells.

PMID: 19789339 [PubMed - indexed for MEDLINE]

Proteasome inhibition with bortezomib suppresses growth and induces apoptosis in osteosarcoma

James Street — Wed, 11 Aug 2010 05:55:56 +0000

* 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]

Fish Oil And Cancer – New Findings

James Street — Sun, 06 Jun 2010 16:32:31 +0000

June 6, 2010

Swedish scientists recently published an important paper on the positive impact of omega-3 fatty acids (which are found mainly in fish oil) on a certain type of childhood cancer called neuroblastoma (Gleissman 2010). These Karolinska Institute scientists had previously shown that DHA (the most unsaturated form of fatty acid in fish oil) could cause apoptosis (i.e., programmed cell death) in cancer cells. They have now extended their work to experimental animals, showing that fish oil supplementation caused either stabilization or actual regression of tumors in these animals. As they state, DHA “is a promising new agent for cancer treatment and prevention of minimal residual disease” (ibid). Their conclusions, as I shall show, also have relevance to a broader range of adult cancers.
The paper actually encompasses two parts, one on treatment, the other on prevention. In the prevention half, they gave DHA as a food supplement to rats before the animals were implanted with human neuroblastoma cells. (Because they lack a thymus, the rats in question are unable to reject tissue from a foreign species.) In the treatment half of the study, athymic rats that already had established neuroblastomas were force fed DHA daily and their tumor growth and DHA levels were then monitored. The authors concluded that “untreated control animals developed progressive disease, whereas treatment with DHA resulted in stable disease or partial response.” The response depending on the dose of DHA.
Neuroblastoma is a tumor of the sympathetic nervous system that occurs in children. In fact, it accounts for 6 to 9 percent of all childhood cancers. It is the most deadly solid tumor of childhood outside the brain. “Despite intensive treatment modalities, the cure rate for these patients is less than 50 percent,” the authors report, “and the majority experience relapse from minimal residual disease.” Needless to say, there is an urgent need for new treatment ideas.
There appears to be a very special relationship between DHA and nerve tissue. For instance, a deficiency of DHA will lead to delayed neural development. Compared to normal nerve tissue, neuroblastoma is “profoundly deficient in DHA,” whereas the level of the competing omega-6 fatty acid arachidonic acid (AA) is increased. This suggested to the authors that “an imbalance between omega-3 and omega-6 fatty acids may serve as an adaptation mechanism in nervous system tumors.” Logically, then, one might expect the addition of DHA to slow or even stop the growth of neuroblastoma.
This is indeed what happened when they gave DHA supplements. The authors reported: “In the DHA-supplemented group the mean time to tumor take was significantly delayed compared to the control group” (ibid.). One rat receiving the DHA-enriched diet did not develop tumors at all. In the treatment part of the study, the median tumor volume index at the end of the experiment (day 12) was 3.72 for animals receiving one gram of DHA per kilogram of body weight, 5.47 for animals receiving half a gram per kilogram of DHA, and 9.48 in the control animals. The results were statistically significant. Put another way, a high dose of DHA decreased normal tumor growth by about two-thirds. As was predicted in the authors’ ‘omega-3 deficiency’ theory, the level of DHA in the tumor tissue tripled in the higher-dose treatment group vs. the controls.

TO BE COMPLETED, WITH REFERENCES, NEXT WEEK.

–Ralph W. Moss, Ph.D.

University of Miami developing potent weapon against cancer

James Street — Wed, 19 May 2010 05:46:34 +0000

Eli Gilboa, Ph.D., co-leader of the Tumor Immunology Program at Sylvester Comprehensive Cancer Center

Photo

BY FRED TASKER

ftasker@MiamiHerald.com

University of Miami doctors have developed a new method of catching and killing tumor cells floating through the human bloodstream they say could be a potent new weapon against most kinds of cancer within a decade.

“This will be a big advance — powerful, simpler to carry out, cheaper and broadly applicable to virtually any cancer,” says Eli Gilboa, Ph.D., co-leader of the Tumor Immunology Program at Sylvester Comprehensive Cancer Center.

After a cancerous tumor is excised from a patient’s breast, lung, prostate or other organ by surgery or radiation, there starts an agonizing wait to see if it has metastasized, or spread, to other parts of the body.

The UM medical team’s new approach is to get the body’s immune system to catch and kill the roaming cancer cells before they can affect other organs. The study appears in the May issue of the peer-reviewed journal Nature.

The doctors acknowledge that the concept has been limited to laboratory test tubes and animals, and faces up to 10 years of human testing before general use.

In healthy people, the immune system is a powerful defense against disease, identifying tumor cells by spotting antigens, which are foreign chemical substances attached to the tumors.

The problem: Many tumors don’t have enough antigens to trigger the immune system. When tumors are small, the immune system is not properly activated, Gilboa says.

“Oncology knows how to get rid of big tumors you can see and surgically remove or radiate,” Gilboa said. “Most patients die when the disease spreads to areas we don’t know about or can’t access. This is where the immune system has the advantage.”

Gilboa and his team manipulated the body’s DNA and RNA to induce the cancer cells scattered through the body to “express,” or produce, more antigens. It makes them easier to spot by the immune system.

In the lab, the process eliminated tumors in rats.

Dr. Richard Jove, deputy director of the Comprehensive Cancer Center at the City of Hope Medical Center in Los Angeles, called the work a “fundamental breakthrough that could be applied to any cancer.”

“The challenge for decades has been that the immune system has been tolerant to the antigens on tumor cells. It’s why tumor immunotherapy has not been particularly successful to date,” said Jove, who was not involved in the UM study.

Gilboa’s UM team includes Fernando Pastor, post-doctoral associate at Sylvester; Despina Kolonias, senior research associate at Sylvester; and Paloma Giagrande, assistant professor of internal medicine at the University of Iowa.

Cancer killed 562,000 Americans in 2009, making it the second biggest disease killer after heart disease, according to the American Cancer Society.

Platinum-based cancer drugs (cisplatin) destroy tumor cells by binding to DNA strands

James Street — Thu, 15 Apr 2010 02:06:59 +0000

Platinum-based cancer drugs destroy tumor cells by binding to DNA strands

April 14, 2010 by Anne Trafton

For 30 years, the chemotherapy drug cisplatin has been one of doctors’ first lines of defense against tumors, especially those of the lung, ovary and testes. While cisplatin is often effective when first given, it has a major drawback: Tumors can become resistant to the drug and start growing again.

Now, MIT cancer biologists have shown how that resistance arises, a finding that could help researchers design new drugs that overcome cisplatin resistance. The team, led by Tyler Jacks, director of the David H. Koch Institute for Integrative Cancer Research at MIT, reports the results in the April 15 issue of the journal Genes and Development.

Cisplatin and other platinum-based cancer drugs destroy tumor cells by binding to DNA strands, interfering with DNA replication. That activates the cell’s DNA repair mechanisms, but if the damage is too extensive to be repaired, the cell undergoes programmed suicide.

Eventually, cancer cells learn to fight back. The new study shows that tumor cells treated with cisplatin ramp up their DNA repair pathways, allowing them to evade cell death, says Trudy Oliver, a postdoctoral fellow in Jacks’ lab and lead author of the paper.

Previous studies had suggested several possible mechanisms for resistance development, including enhancement of DNA repair pathways, detoxification of the drug, and changes in how the drug is imported into or exported out of the cell. However, those studies were done in cancer cells grown in the lab, not in living animals (in vivo).

“Many mechanisms have been identified but it’s not clear what happens in vivo because the in vivo environment is so much more complicated than in cell lines,” says Oliver.

Oliver and her colleagues set out to study cisplatin resistance in mice with a mutation in a gene called Kras, which leads the animals to develop lung cancer. About 30 percent of human lung cancer patients have mutations in Kras. Some of the mice also had defective versions of the tumor suppressor gene p53, which is mutated in about half of human lung cancers.

The researchers found that cisplatin was effective against lung tumors in both sets of mice, though it was more potent in mice that still had functional p53. In those mice, tumors actually shrank, while the drug only slowed tumor growth in mice with defective p53. Those results are consistent with findings in human patients.

After four doses of cisplatin, mice with normal p53 developed resistance to the drug, and tumors started growing faster. To figure out why, the researchers analyzed which genes were being transcribed more as resistance developed, and identified several that are involved in DNA repair pathways.

One gene that particularly caught the researchers’ attention is PIDD (p53-induced protein with a death domain), which is turned on by p53 and has been implicated in programmed cell death, though its exact function is not known. When PIDD levels are artificially increased in human lung cancer cells, they become more resistant to cisplatin.

Oliver is now studying tumors in which the PIDD gene has been knocked out, to see if its absence hinders drug resistance. It is likely that PIDD is just one of many genes, in many pathways, involved in the drug resistance process, says Oliver. “It’s not a simple phenomenon,” she says.

More information: “Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer,” Trudy Oliver, Kim Mercer, Leanne Sayles, James Burke, Diana Mendus, Katherine Lovejoy, Mei-Hsin Cheng, Aravind Subramanian, David Mu, Scott Powers, Denise Crowley, Roderick Bronson, Charles Whittaker, Arjun Bhutkar, Stephen Lippard, Todd Golub, Juergen Thomale, Tyler Jacks and Alejandro Sweet-Cordero; Genes and Development.

Provided by Massachusetts Institute of Technology (news : web)

Ketoprofen reduces Osteosarcoma metastases and tumor growth rate in mouse xenograft models

James Street — Fri, 26 Feb 2010 06:04:58 +0000

Effect of Ketoprofen in Topical Formulation on Vascular Endothelial Growth Factor Expression and Tumor Growth in Nude Mice With Osteosarcoma

Abstract

OST cells, a low metastatic cell line established from human osteosarcoma, were inoculated under the periosteum of the ossa cranii of nude mice. Four weeks later, tumors were percutaneously treated for an additional 4 weeks with a patch containing either placebo or ketoprofen (KP). In the placebo group, OST cells formed osteoid and invaded the cranial bone. Tumor mass weighed 3.54 g. Approximately 85% of cells within the tumor expressed proliferating cell nuclear antigen (PCNA), indicating that they were proliferating with a high mitotic activity. Many feeder vessels were located within the tumor. The majority of tumor cells expressed intensely vascular endothelial growth factor (VEGF). In the KP group, invasion of OST cells into the cranial bone was suppressed and the tumor mass was 47% of that of the placebo group. Approximately 65% of cells within the tumor were PCNA-negative, indicating that their growth was arrested. There were considerably fewer feeder vessels within the tumor in the KP group than in the placebo group. Only a small number of cells expressed VEGF. Based on these findings, we concluded that topical administration of KP to nude mice with Osteosarcoma inhibited VEGF expression, reduced the development of feeder vessels for supply of nutrients and oxygen, and suppressed tumor growth.

Keywords: Osteosarcoma; Ketoprofen; Topical formulation; Tumor growth; Vascular endothelial growth factor

For the complete article, please see the Physician Web page Physician Web page