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Research Corner Abstracts by Tom Swartz and Bruce Shriver
In this issue:
Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway Malignant fibrous histiocytoma (MFH), now termed high-grade undifferentiated pleomorphic sarcoma, is a commonly diagnosed mesenchymal tumor, yet both the underlying molecular mechanisms of tumorigenesis and cell of origin remain unidentified. The investigators of this study present evidence demonstrating that human mesenchymal stem cells (hMSCs) are the progenitors of MFH. DKK1, a Wnt inhibitor and mediator of hMSC proliferation, is overexpressed in MFH. Using recombinant proteins, antibody depletion, and siRNA knockdown strategies of specific Wnt elements, they show that DKK1 inhibits hMSC commitment to differentiation via Wnt2/ß-catenin canonical signaling and that Wnt5a/JNK noncanonical signaling regulates a viability checkpoint independent of Dkk1. Finally, they illustrate that hMSCs can be transformed via inhibition of Wnt signaling to form MFH-like tumors in nude mice, and conversely, MFH cells in which Wnt signaling is appropriately reestablished can differentiate along mature connective tissue lineages. Their results provide mechanistic insights regarding the cell of origin of MFH, establish what they believe is a novel tumor suppressor role for Wnt signaling, and identify a potential therapeutic differentiation strategy for sarcomas.
Chemobrain: is systemic chemotherapy neurotoxic? The existence of chemobrain has become almost universally accepted, although many details of the concept are controversial. Data about the different types of cognitive impairment and their duration are not always consistent in the literature. We still do not know which cytotoxic agents are responsible, which characteristics make patients vulnerable, and which biologic mechanisms are involved. Through this review of the recent literature, the authors provide an actualized definition of chemobrain including recent functional imaging data and debate its controversial aspects. Then, the hypotheses underlying the cause and potential treatment of chemobrain will be discussed and eventually, propositions for better designed future trials, in order to obtain a better understanding of chemobrain, will be proposed through the recent data of the literature.
Compassionate use of bevacizumab (Avastin®) in children and young adults with refractory or recurrent solid tumorsThe aim of this study was to evaluate feasibility and toxicity of bevacizumab (Avastin®), a monoclonal antibody directed against the vascular endothelial growth factor in children and young adults. Fifteen patients (male: n = 8; female: n = 7; median age, 14.6 years) received bevacizumab for recurrent or progressive solid tumors (carcinoma: n = 3; neuroblastoma: n = 2; astrocytoma grade III: n = 2; rhabdomyosarcoma: n = 2; nephroblastoma: n = 2; benign vascular tumors: n = 2; synovial sarcoma: n = 1; and malignant hemangiopericytoma: n = 1) on a compassionate basis. Bevacizumab was administered at 5–10 mg/kg body weight intravenously every 2–3 weeks. Most patients received chemotherapy in addition to bevacizumab. Duration of bevacizumab therapy ranged from 1.5 to 23 months. Results were as follows: Bevacizumab-related side-effects were mild and included hypertonia (n = 2), proteinuria/hematuria (n = 2), epistaxis (n = 2), local erythema (n = 1), and defective wound healing and ascites (n = 1). Radiographic objective responses (partial responses) were observed in two patients with astrocytoma grade III and in one patient each with neuroblastoma and pleomorphic rhabdomyosarcoma, respectively. The investigators Conclude: Bevacizumab seems to have a good acute safety profile and some antitumor activity in heavily pretreated children and young adults with recurrent solid tumors. Prospective clinical trials are urgently needed to further evaluate the safety and efficacy of bevacizumab in pediatric patients.
The objective of this study was to evaluate the impact of positron emission tomography (PET) using fluorine-18–fluorodeoxyglucose (FDG) for initial staging and therapy planning in pediatric sarcoma patients. In this prospective multicenter study, 46 pediatric patients (females, n = 22; males, n = 24; age range, 1 to 18 years) with histologically proven sarcoma (Ewing sarcoma family tumors, n = 23; osteosarcoma, n = 11; rhabdomyosarcoma, n = 12) were examined with conventional imaging modalities (CIMs), including ultrasound, computed tomography (CT), magnetic resonance imaging, and bone scintigraphy according to the standardized algorithms of the international therapy optimization trials, and whole-body FDG-PET. A lesion- and patient-based analysis of PET alone and CIMs alone and a side-by-side (SBS) analysis of FDG-PET and CIMs were performed. The standard of reference consisted of all imaging material, follow-up data (mean follow-up time, 24 ± 12 months), and histopathology and was determined by an interdisciplinary tumor board. The Results were as follows: FDG-PET and CIMs were equally effective in the detection of primary tumors (accuracy, 100%). PET was superior to CIMs concerning the correct detection of lymph node involvement (sensitivity, 95% v 25%, respectively) and bone manifestations (sensitivity, 90% v 57%, respectively), whereas CT was more reliable than FDG-PET in depicting lung metastases (sensitivity, 100% v 25%, respectively). The patient-based analysis revealed the best results for SBS, with 91% correct therapy decisions. This was significantly superior to CIMs (59%; P < .001). The authors Conclude: In staging pediatric sarcoma, subsidiary FDG-PET scanning depicts important additional information and has a relevant impact on therapy planning when analyzed side-by-side with CIMs.
Novel Mechanism For Spread Of Sarcoma Tumors Discovered A team of researchers at the National Cancer Institute (NCI), using a mouse model, have uncovered a novel protein interaction that promotes the spread of cancer cells (a process known as metastasis) in a class of tumors collectively called sarcomas. In doing so, they have found the first instance in which the modification and destruction of a protein, rather than a failure to make the protein, drives the spread of cancer.
"These results add an entirely new perspective to our understanding of metastasis, and highlight the importance of studying mechanisms beyond gene expression in defining and addressing the reasons for cancer progression," said NCI Director John E. Niederhuber, M.D.
To metastasize, cancer cells must escape the original tumor, enter and exit the bloodstream or lymphatic system, and successfully colonize a new target organ or tissue. These steps require the activation and/or deactivation of numerous genes that play a variety of roles (e.g., cell migration, cell signaling, and adhesion).
Research into the root causes of metastasis has traditionally focused on genetic or genomic changes, such as the loss of genes that inhibit metastasis or the overexpression of genes that promote it. The NCI team from the Center for Cancer Research (CCR), led by Allan Weissman, M.D., chief of the Laboratory of Protein Dynamics and Signaling, and by Chand Khanna, Ph.D., head, of the Tumor and Metastasis Biology Section in the Pediatric Oncology Branch, took a different approach in this study. Instead of examining gene-based mechanisms, the NCI team focused on chemical changes that are made to protein products after they have been translated from their genes. Such changes, called post-translational modifications, can significantly alter a protein's function or fate.
Weissman, Khanna, and colleagues started with a protein known as gp78, which tags specific proteins with ubiquitin. Ubiquitylation can lead to the destruction of tagged proteins by a complex cellular machine called the proteasome. Cells use ubiquitylation as a means to regulate the levels of critical proteins within the cells as well as to remove unnecessary and damaged proteins.
By silencing the activity of gp78, the NCI team found that the spread and survival of cancer cells in animal models was greatly reduced. The researchers also discovered that gp78 interacts with another protein called KAI1, a protein which has previously been shown to interfere with metastasis and is categorized as a metastasis suppressor. In the model the researchers used, silencing gp78 in sarcoma cells caused levels of KAI1 to rise, and decreased cancer cell survival. Conversely, in sarcoma cells with high levels of gp78, KAI1 was more frequently tagged for destruction. The scientists found that this silencing of KAI1 in cancer cells encouraged both cancer cell survival and metastasis.
Going a step further, the NCI team examined archived sarcoma tumor samples from patients, and found that tumors with low levels of gp78 had higher levels of KAI1, and that tumors with high levels of gp78 had lower levels of KAI1. While the number of sarcomas sampled was relatively small, the result suggests that KAI1 ubiquitylation by gp78 could play a role in cancer spread in human sarcoma. This leads to the question of how ubiquitylation of proteins by gp78 might affect other human cancers.
"This is the first example of how ubiquitylation can impact metastasis by altering the level of a metastasis suppressor" said Weissman. "These findings offer a rationale for the use of current proteasome inhibitors, such as bortezomib, and for the development of drugs that interfere with ubiquitylation to treat metastatic cancers." The study is published in Nature Medicine Vol. 13, No.12.
Expression of receptor tyrosine kinases and apoptotic molecules in rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a rare mesenchymal tumor with few treatment options after the failure of first-line therapy. Understanding the expression of kinases and apoptotic molecules in RMS tumors may lead to elucidation of mechanisms of resistance to chemotherapy and development of new therapies. In this study, paraffin-embedded tissue samples were collected from 105 RMS patients treated at the M. D. Anderson Cancer Center and examined for the immunohistochemical expression of kinases and apoptotic molecules deemed potential therapeutic targets. Clinicopathologic information was collected on all patients and analyzed for correlation with overall survival (OS). The Results were follows: Of the 105 patients, 44 (42%) were female and 89 (85%) were older than 10 years of age. The 5-year OS for this cohort was 24.7%, with inferior median OS in patients with genitourinary primary tumors and those with invasion through the deep fascial plane. Immunohistochemistry revealed Kit and c-erb-b2 to be present on < 10% of tumors but EGFR, PDGFR-, PDGFR-, Bcl-2, and Bax were present in > 40% of tumors. Patients whose tumors expressed PDGFR- were found to have a shorter median OS by multivariate analysis (26 vs. 266 months, P = .076). Conversely, patients whose tumors expressed Bax were found to have a longer OS (31 vs. 19 months, P = .047). The authors Conclude: EGFR, PDGFR-, PDGFR-, Bcl-2, and Bax are frequently expressed in human RMS tissue and may represent new therapeutic targets. Absence of PDGFR- and the presence of Bax are associated with a longer median OS in patients with RMS. Targeting these molecules may be a successful therapeutic strategy.
Phase 1 and Pharmacokinetic Study of Lexatumumab in Patients with Advanced Cancers The purpose of this Phase I trial was to assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of lexatumumab (HGS-ETR2), a fully human agonistic monoclonal antibody which targets and activates the tumor necrosis factor–related apoptosis-inducing ligand receptor 2 (TRAIL-R2) in patients with advanced solid malignancies. In this open label study, patients with advanced solid malignancies were treated with escalating doses of lexatumumab administered i.v. over 30 to 120 min every 21 days. A cohort of four patients, which could be expanded to six patients, was studied at each dose level. The dose-limiting toxicity (DLT) dose was defined as the dose at which the incidence of DLT in the first two cycles was 33%. The maximum tolerated dose was defined as the highest dose at which <33% of subjects experienced DLT. The pharmacokinetics and immunogenicity of lexatumumab were also characterized. Tumor specimens from historical or current biopsies, when available, were stained for TRAIL-R2 using immunohistochemistry techniques. The Results were as follows: Thirty-seven patients received 120 cycles of lexatumumab at doses ranging from 0.1 to 20 mg/kg every 21 days as of May 2006. The 20 mg/kg dose was identified as the DLT dose based on DLTs in three of seven patients treated with this dose; DLTs included asymptomatic elevations of serum amylase, transaminases, and bilirubin. The 10 mg/kg dose cohort was expanded to 12 patients and the 10 mg/kg dose was identified as the maximum tolerated dose. The mean (±SD) clearance and apparent terminal half-life values at the 10 mg/kg dose averaged 6.0 (2.9) mL/d/kg and 16.4 (10.9) days, respectively. Twelve patients had durable stable disease that lasted a median of 4.5 months, including three patients with sarcoma having prolonged stable disease (6.7 months). Immunohistochemistry for TRAIL-R2 showed specific staining in >10% of tumor cells for 16 of the 20 evaluable specimens submitted (80%). The Investigators Conclude: Lexatumumab was safe and well tolerated at doses up to and including 10 mg/kg every 21 days. Lexatumumab was associated with sustained stable disease in several patients. Pharmacokinetics were linear over the dose range studied, and consistent with a two-compartment model with first-order elimination from the central compartment. Additional evaluation of this novel apoptosis-inducing agent, particularly in combination with chemotherapy agents, is warranted and ongoing.
Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-kappaB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors. Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily. The Results were as follows: No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease. The investigators Conclude: The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated. Trial registration number NCT00290680.
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