|
|
              
 |
Research Corner
annotations by
Tom Swartz
FDA Approves Genotype Test for Drug Response [No longer available on website 10/2005] The Food and Drug Administration has approved the first DNA microarray test that indicates whether a patient is more or less likely to experience side effects from several common heart drugs, antidepressants and chemotherapy agents. The AmpliChip Cytochrome P450 Genotyping test for use with the Affymetrix GeneChip Microarray Instrumentation System will not indicate definitively whether a patient will benefit from or be harmed by a particular agent, and the FDA approval includes the caveat that it should not be used as a stand-alone tool. The agency has only cleared the test for use in conjunction with clinical evaluation and other tools to determine the best options for a patient. Experts expect that, at least initially, this test will primarily offer a reason why a patient is responding in one way or another. For more information on the The AmpliChip CYP450 Test, click here.
Radiotherapy for Local Control of Osteosarcoma Local control of osteosarcoma in patients for whom a resection with satisfactory margins is not achieved can be difficult. The investigators of this study evaluated the efficacy of radiotherapy in this setting. They identified 41 osteosarcoma patients that either were not resected or were excised with close or positive margins and who underwent radiotherapy with external beam photons and/or protons between 1980 and 2002. These patients’ charts were reviewed to assess local control, progression-free survival, metastasis-free survival, and overall survival. The anatomic sites treated were as follows: head/face/skull (17), extremity (8), spine (8), pelvis (7), and trunk (1).
Of the 41 patients, 27 (65.85%) had undergone gross total tumor resection, 9 (21.95%) subtotal resection, and 5 (12.2%) biopsy only. Chemotherapy was given to 35 patients (85.4%). Of the 41 patients, 27 (65.85%) were treated for localized disease at primary presentation, 10 (24.4%) for local recurrence, and 4 (9.8%) for metastatic disease.
The overall local control rate at 5 years was 68% +/- 8.3%. The local control rate according to the extent of resection was 78.4% +/- 8.6% for gross total resection, 77.8% +/- 13.9% for subtotal resection, and 40% +/- 21.9% for biopsy only. The overall survival rate according to the extent of resection was 74.45% +/- 9.1% for gross total resection, 74.1% +/- 16.1% for subtotal resection, and 25% +/- 21.65% for biopsy only. Patients with either gross or subtotal resection had a greater rate of local control, survival, and disease-free survival compared with those who underwent biopsy only at 5 years (77.7% +/- 7.5% vs. 40% +/- 21%, 73.9% +/- 8.1% vs. 25% +/- 21.6%, and 51.9% +/- 9.1% vs. 25% +/- 21.6%, respectively). Overall survival was better in patients treated at primary presentation (78.8% +/- 8.6% compared with 54% +/- 17.3% for recurrence).
No definitive dose-response relationship for local control of tumor was seen, although the local control rate was 71% +/- 9% for 32 patients receiving radiation doses >/=55 Gy vs. 53.6% +/- 20.1% for 9 patients receiving <55 Gy. Of 15 patients with tumors >5.3 cm, 9 received doses >/=55 Gy and the local control rate was 80% +/- 17.9%, and 6 received doses < 55 Gy with a local control rate of only 50% +/- 25% at 5 years. Among patients who underwent gross total resection, the local control rate was 77.5% +/- 9.95% in 22 patients with negative margins vs. 66.7% +/- 27.2% in 3 patients with positive margins. Two patients had unknown margin status.
The investigators of this study thus concluded that radiotherapy can help provide local control of osteosarcoma for patients in whom surgical resection with widely, negative margins is not possible. It appears to be more effective in situations in which microscopic or minimal residual disease is being treated.
New Gene Test Identifies Tumors of Unknown Origin Between 3 and 15 percent of newly diagnosed cancers in the U.S. each year are classified as tumors of unknown origin (TUO), meaning simply that the type of cancer cannot be readily identified. Since most cancer treatments are selected specifically for the type of tumor, when the tumor type is unknown, selection of treatment is difficult or impossible which means the patient loses precious time. Equally important is being able to identify a tumor as a recurrence or another primary tumor. Diagnosing tumors of unknown origin has traditionally been a complex, costly and inexact process; only 25 to 30 percent of all TUOs are successfully identified using traditional diagnostic methods. However, US LABS recently introduced a new testing methodology for identification of tumors of unknown origin. Currently available only for research applications, this new test uses a technology called Gene Expression Profiling, a type of genomics testing. The test has exhibited an 86 percent accuracy rate. Gene Expression Profiling is performed on a patient's RNA sample that is put through what is called laser capture microdissection. This process allows for an enriched sample of the tumor to be selected that actually increases the yield of RNA for analysis. A series of steps are performed on the RNA resulting in a gene expression. This expression is then compared by the US LABS system to over 60 different kinds of cancer, 24 tissue or organ sites and 69 tumor types accounting for more than 90 percent of all known cancers.
Different Patterns of Angiogenesis in Sarcomas and Carcinomas Solid tumors depend on angiogenesis for growth and metastasis. It has been shown that blood vessel density, as determined by counting the number of capillaries in clustered bursts, is a significant prognostic factor in carcinomas. It has been unclear, however, whether vessel density is a prognostic factor in sarcomas. The investigators of this study examined angiogenesis in sarcomas of various grades and compared their vascular patterns to those of carcinomas. The investigators found that in breast carcinomas, capillaries were clustered in bursts within the stroma of the tumor, whereas the sarcoma capillaries were homogeneously distributed in the tumor stroma. The investigators believe that this difference in the pattern of angiogenesis in sarcomas and carcinomas may be attributable to the presence of fibroblasts and myofibroblasts in carcinomas, resulting in the compartmentalization of bursts of angiogenic factors. Whereas the homogeneous appearance of vessel density in sarcomas observed in the study would be the consequence of the influence of a single compartment.
Note: For an explanation of the structure of solid tumors see Solid Tumor Structure and Tumor Stroma Generation. This is a chapter pf the book, Cancer Medicine e.5, published by B.C. Decker Inc. (click on the title to access the complete book). This is an excellent, readable text for the general reader.
"Philinopside A" is a is a novel compound isolated from the sea cucumber, Pentacta quadrangulari. The investigators of this study evaluated the effects of philinopside A on angiogenesis and tumor growth in a series of models in vitro and in vivo. Their results demonstrated that philinopside A significantly inhibited the proliferation, migration and tube formation of human microvascular endothelial cells (HMECs) in a dose-dependent manner. An examination of the effects of philinopside A on the angiogenesis-related receptor tyrosine kinases (RTKs) also showed that philinopside A broadly inhibited all tested RTKs. In addition, philinopside A demonstrated strong anti-tumor activities both in vitro and in vivo. The investigators found that the compound reduced mouse sarcoma 180 tumor volume by inducing apoptosis of tumor and tumor-associated endothelial cells. Thus, the investigators believe that their results suggest that philinopside A is a promising anti-cancer agent that possesses dual cytotoxic and anti-angiogenic effects.
Biology and Therapeutic Advances for Pediatric Osteosarcoma This paper describes current strategies for treating patients with osteosarcoma as well as review of the clinical features, radiologic and diagnostic work-up, and pathology. The authors review the state of the art management for patients with osteosarcoma in North America and Europe including the use of limb-salvage procedures and reconstruction as well as discuss the etiologic and biologic factors associated with tumor development. Therapy-related sequelae and future directions in the biology and therapy for these patients are also discussed.
The investigators of this study examined the effect of a unique mixture of nutrients containing lysine, proline, arginine, ascorbic acid, and epigallocatechin gallate (EGCG) on human osteosarcoma and Ewing’s sarcoma cell lines by measuring: cell proliferation, expression of matrix metalloproteinase-2 (MMP-2), MMP-9, and invasive and angiogenesis potential. Their results suggest that nutrient synergy is an excellent candidate for therapeutic use in the treatment of osteosarcoma, by inhibiting cancer cell invasion, and secretion of MMPs and VEGF, all critical parameters for cancer control and prevention.
Tumor Angiogenesis and Outcome in Osteosarcoma Angiogenesis (the formation of blood vessels) quantified by microvessel density has been shown to be a strong prognostic indicator in a number of cancers. However, its association with prognosis in bone sarcomas has been subject to less extensive research. Thus, the investigators of this study sought to investigate the prognostic significance of angiogenesis in osteosarcoma by measuring microvessel density. The result of the study indicates that the rate of metastasis was significantly higher in patients with high microvessel counts, and thus angiogenesis is predictive of poor prognosis in osteosarcoma.
The investigators of this study examined the role of human apurinic endonuclease 1 (APE1) in osteosarcoma tumor cell resistance and prognosis. Sixty human osteosarcoma samples were analyzed. APE1 protein was elevated in 72% of these samples, and among those with a known clinical outcome, there was a significant correlation between high APE1 expression levels and reduced survival times. The remaining 28% of samples showed low expression of APE1. Given that APE1 was over expressed in osteosarcoma, the investigators then decreased APE1 levels using silencing RNA (siRNA) targeting technology to enhance chemo- and radiation sensitivity. Using this siRNA targeted technology of APE1, protein levels were reduced by more than 90% within 24 hours, remained low for 72 hours, and returned to normal levels at 96 hours. There was also a clear loss of APE1 endonuclease activity following APE1-siRNA treatment. A decrease in APE1 levels in siRNA-treated human osteosarcoma cells led to enhanced cell sensitization to the DNA damaging agents: methyl methanesulfonate, H2O2, ionizing radiation, and chemotherapeutic agents. Thus, the investigators believe these findings have both prognostic and therapeutic implications for treating osteosarcoma, and that the APE1-siRNA results demonstrate the feasibility for the therapeutic modulation of APE1 using a variety of molecules and approaches.
The melanoma cellular adhesion molecule, also known as MUC18, is highly expressed on several tumors, including osteosarcoma and Ewing’s sarcoma. The level of MUC18 expression has been found to correlate directly with tumor progression and metastatic potential. These observations have established MUC18 as a candidate mediator of tumor growth and metastasis, and suggest that blockade of MUC18 might be a potential target for immunotherapy against several MUC18-expressing tumors, including human bone sarcomas. The investigators of this study developed a fully human anti-MUC18 antibody, ABX-MA1, and studied the effect of ABX-MA1 on growth, adhesion, invasion, and metastasis of human osteosaroma cells both in vitro and in vivo. The investigators found that ABX-MA1 had no effect on the proliferation of osteosarcoma cells in vitro, nor did it significantly inhibit the growth of KRIB human osteosarcoma cells when they were orthotopically implanted into the tibias of nude mice. However, after 6 weeks, significantly fewer ABX-MA1-treated mice developed spontaneous pulmonary metastases than did IgG-treated control mice. Additionally, ABX-MA1 decreased the invasion of osteosarcoma cells through Matrigel-coated filters and disrupted homotypic adhesion between osteosarcoma cells and their heterotypic interaction with human vascular endothelial cells. Thus, the investigators conclude that MUC18 plays a central role in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by ABX-MA1 may be a novel immunotherapeutic approach in the management of osteosarcoma.
Altered Expression and Deletion of RMO1 in Osteosarcoma In order to increase understanding of the molecular events underlying osteosarcoma progression, the investigators of this study examined the expression of approximately 950 genes in 24 primary and metastatic osteosarcoma tumor specimens. A gene, RMO1, was isolated with decreased expression in metastatic samples. RMO1 is located at chromosome 2q33, a region of frequent loss of heterozygosity in cancer, and exhibited loss of heterozygosity in 6 out of 9 primary osteosarcoma tumor samples (67%). Loss of heterozygosity is evident in primary tumors while the decrease in gene expression is seen in the metastatic samples, indicating that these 2 events are separately implicated in cancer progression. Thus, the investigators of this study believe that RMO1 may be a candidate for a protein involved in inhibiting tumor progression.
Nuclear Receptor Agonists as Potential Differentiation Therapy Agents for Human Osteosarcoma
The
investigators of this study examined whether nuclear receptor
agonists can be used as potential differentiation therapy agents
for human
osteosarcoma.
Four
osteosarcoma
cell lines were treated with proliferator-activated receptor (PPAR)
V2N1 ESUN Copyright © 2005 Liddy Shriver Sarcoma Initiative.
|
agonists,
troglitazone and ciglitazone, and a retinoid X receptor (RXR)
ligand, 9-cis retinoic acid. The investigators found that on
treatment with the PPAR
