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.

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.

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.

PMID: 19789339 [PubMed - indexed for MEDLINE]

Artemisinin Blocks Prostate Cancer Growth and Cell Cycle Progression by Disrupting Sp1 Interactions with the Cyclin-dependent Kinase-4 (CDK4) Promoter and Inhibiting CDK4 Gene Expression^*

HOUSTON-A receptor known to be active in bone metastases, but previously unexplored in primary bone tumors, is a potential therapeutic target in osteosarcoma, investigators from The University of Texas M. D. Anderson Cancer Center report in the March 1, 2009 issue of Cancer Research.

The researchers found that the protein – interleukin-11 receptor alpha (IL-11Ra) – is highly expressed in primary osteosarcoma and in lung metastases from these tumors.

Their research suggests the possibility of delivering therapeutic agents directly to osteosarcoma cells by targeting the receptor with circulating particles that display a peptide mimic of the natural ligand that binds IL-11Ra.

Osteosarcoma is the most common primary malignant tumor of bone. “Existing treatment has not changed the prognosis for osteosarcoma for the last 20 to 30 years,” said lead investigator Valerae O. Lewis, M.D., associate professor and chief of Orthopedic Oncology at M. D. Anderson. “About 30 percent of patients still relapse and die of their disease. New therapeutic strategies and agents are needed.”

The effectiveness of the current chemotherapy regimens for osteosarcoma is limited by toxic side effects, including damage to the heart and nerves, kidney failure and hearing loss, Lewis noted.

Identification of a target specific for osteosarcoma cells opens the door for the development of therapies that can shut down the tumor cells without inflicting the collateral damage caused by conventional osteosarcoma treatments.

IL-11Ra is a target in bone metastasis; far less is known about its attributes, if any, in primary tumors of bone. To address IL-11R? as a potential molecular target in osteosarcoma, the authors confirmed the protein expression and localization of IL-11Ra in several mouse and human osteosarcoma cell lines.

In an orthotopic mouse model of human osteosarcoma, the investigators found that the IL-11Ra not only was markedly present in the primary osteosarcoma and in its metastases but was absent from normal bone marrow and lungs.

To evaluate the accessibility of IL-11Ra as a target, the researchers intravenously administered small, virus-like particles called phages equipped with a peptide that mimics IL-11, the receptor’s natural ligand. After 24 hours in circulation, the ligand-directed particles were taken up in the tumors but showed little or no accumulation in several control organs.

“Connecting therapeutic agents to this ligand-directed system might result in improved, targeted drugs,” said co-senior author Renata Pasqualini, Ph.D., Professor of Medicine and Cancer Biology in the David H. Koch Center at M. D. Anderson.

“It is conceptually unexpected that a receptor would be over-expressed not only in metastatic tumors to bone but also in primary bone tumors; this is quite important because human osteosarcoma is a malignant tumor with very few targets at the protein level,” said co-senior author Wadih Arap, M.D, Ph.D., also Professor of Medicine and Cancer Biology in the David H. Koch Center.

Immunohistochemical staining analysis of IL-11Ra expression in primary and metastatic human osteosarcoma samples provided further evidence of the potential value of IL-11Ra as a therapeutic target.

All primary human osteosarcoma samples exhibited moderate-to high-intensity staining of tumor cells. More than half of tumor blood vessels also showed moderate-to-high-intensity staining. All pulmonary metastases were positive for IL-11Ra expression, while normal, control lung tissue was negative.

“This indicates that therapeutic targeting of IL-11Ra may yield anti-tumor, anti-metastasis and anti-angiogenesis effects in osteosarcoma,” Lewis said.

The U.S. Food and Drug Administration recently issued “safe to proceed” status for an M. D. Anderson-sponsored investigational new drug based on a cell-death-inducing therapy directed at IL-11R.

The drug is defined as BMTP-11 (Bone Metastasis Targeting Peptide 11). The first clinical trial, in which BMTP-11 will be evaluated in prostate cancer patients, will soon be activated.

Lewis noted that the research group has initiated pre-clinical studies to measure potential anti-tumor effects of BMTP-11 in osteosarcoma models. If successful, such efforts may lead to a rapid evolution of BMTP-11 toward the management of osteosarcoma.

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Research was funded by an M. D. Anderson Institutional Research Grant and a Robert Wood Johnson Foundation grant to Lewis and grants from the National Institutes of Health, the U.S. Department of Defense, the Gillson-Longenbaugh Foundation, and the Marcus Foundation, to Arap and Pasqualini.

Co-authors with Lewis, Arap and Pasqualini are Michael G. Ozawa, in the David H. Koch Center M. D. Anderson and an M.D./Ph.D. student in the Graduate School of Biomedical Sciences, operated jointly by The University of Texas Health Science Center at Houston and M. D. Anderson; Guiyang Wang, of the Department of Orthopedic Oncology; Michael T. Deavers, M.D. of M. D. Anderson’s Department of Pathology; and Tamaki Shintani, D.D.S., Ph.D., of M. D. Anderson’s Department of Radiation Oncology.

Harimaya K, Tanaka K, Matsumoto Y, Sato H, Matsuda S, Iwamoto Y.

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Osteosarcoma is the most frequent malignant bone tumor in children. It is highly invasive, however, the mechanisms behind osteosarcoma cell invasion are as yet still unknown.

In the present study, treatment with TNFalpha enhanced the invasiveness of two human osteosarcoma cell lines, OST and MNNG.

TNFalpha treatment also induced tumor cell motility, adhesion to laminin, the expression of matrix metalloproteinase 9 (MMP9), and the nuclear translocation of nuclear factor kappaB (NFkappaB) in the osteosarcoma cells.

Moreover, antioxidants inhibited TNFalpha-induced osteosarcoma cell invasion, motility and NFkappaB nuclear translocation, but not adhesion to laminin or MMP9 expression.

NFkappaB decoy, another NFkappaB inhibitor, also inhibited TNFalpha-induced osteosarcoma cell invasion and motility.

Therefore, motility and NFkappaB activation were possibly related to TNFalpha-induced osteosarcoma cell invasion.

However, adhesion to laminin or MMP did not demonstrate any correlation with TNFalpha-induced osteosarcoma cell invasion.

Although NFkappaB is known to regulate TNFalpha-induced phenotypes, it may influence only motility and invasion, but not the MMP or laminin-mediated adhesion of these osteosarcoma cells.