M402 at AACR (Hat tip to jq1234 at IHub for digging 'em out first):
>>Abstract Number: 1563
Presentation Title: M402, a heparan sulfate mimetic, inhibits taxane mediated mobilization of endothelial progenitor cells and their homing to tumors in a mouse model
Presentation Time: Monday, Apr 04, 2011, 8:00 AM -12:00 PM
Abstract Body: Treatment with certain anti-cancer agents, particularly taxanes and sunitinib, can lead to mobilization of pro-angiogenic factors and an acute mobilization of Endothelial Progenitor Cells (EPCs), which home to the viable tumor rim where they can enhance tumor vascularization. This phenomenon has been linked to rapid tumor regrowth following chemotherapy or treatment with specific angiogenesis inhibitors and may thus diminish the long-term efficacy of the treatment. EPCs are mobilized in response to circulating growth factors and chemokines (VEGFR, FGF, G-CSF, IL-6, SDF1a, etc.) that are induced by the drug or the progressing tumor. Many of these factors contain heparin binding domains for their anchorage to proteoglycans on cell surfaces or the extracellular matrix. We tested a novel heparan sulfate mimetic, M402, for its ability to inhibit EPC mobilization as well as EPC homing to the tumor as a result of interference with heparin-binding cytokines, chemokines and growth factors. In normal BALB/c mice, G-CSF and Docetaxel induced a significant increase in EPC within 8-24 h of dosing as compared to the saline control, while cisplatin or gemcitabine treatment did not show this effect. The docetaxel-induced EPC mobilization into the blood could be inhibited significantly by M402, similarly to an anti-VEGFR2 antibody (DC101). Analysis of the bone marrow microenvironment indicated that M402 does not inhibit the generation of EPCs but rather prevents the mobilization of EPCs from the bone marrow, likely through disruption of the SDF-1a/CXCR4 axis. M402 alone did not influence EPC mobilization in normal mice. However, in mice bearing orthotopic 4T1 breast carcinoma or Capan-2 pancreatic tumors, treatment with M402 normalized circulating EPCs otherwise mobilized by tumor-secreted factors, particularly G-CSF. Furthermore, M402 inhibited homing of EGFP labeled EPCs into SDF-1a loaded matrigel plugs or 4T1 tumors. The effect on EPCs correlated with decreased tumor angiogenesis as assessed by immuno-histochemistry and microCT. Furthermore, we observed synergistic anti-tumor activity of M402 with docetaxel in the 4T1 model. In conclusion, the experiments show that M402 could inhibit docetaxel or tumor-mediated EPC mobilization by trapping the EPCs in the bone marrow and inhibiting their recruitment into the tumor microenvironment. The data provide a scientific rationale for further studying the observed synergy of M402 with taxanes in cancer patients. <<
For this next one, most of us will have to have a quick look at this first:
"Desmoplasia: This term refers to the growth of fibrous or connective tissue. Some tumors elicit a desmoplastic reaction, the pervasive growth of dense fibrous tissue around the tumor . . ."
medterms.com
Abstract Number: 3113
Presentation Title: M402, a novel heparan sulfate mimetic, modulates the desmoplastic response in an orthotopic pancreatic cancer model in mice
Presentation Time: Tuesday, Apr 05, 2011, 8:00 AM -12:00 PM
Abstract Body: Pancreatic ductal adenocarcinoma (PDAC), currently the fourth leading cause of cancer-related deaths in the US, is one of the most lethal cancers due in part to its resistance to or poor delivery of existing chemotherapeutics (such as gemcitabine). One of the hallmarks of this deadly disease is extensive desmoplasia in the surrounding tumor microenvironment. Recent advances in pancreatic cancer research implicate the involvement of several heparin-binding growth factors that control tumor-stroma interactions (including sonic hedgehog (shh), HB-EGF, TGFs, PDGF and HGF). We have rationally designed a heparan sulfate mimetic, M402, that has previously been shown in animal studies to reduce metastatic seeding through disruption of multiple heparin-binding growth factor-mediated pathways. We hypothesized that M402, alone or in combination with gemcitabine, could potentially modulate tumor-stroma interactions in an orthotopic pancreatic cancer model (Capan-2 cell line) which displays moderate desmoplasia in vivo. Capan-2 human adenocarcinoma cells (~1x106 cells) were injected into the pancreases of immunodeficient mice (Nu/Nu CD-1, female, 8 weeks old). M402 (40 mg/kg/day) or saline treatment commenced on day 4 (via osmotic pump). Gemcitabine (30-60 mg/kg, twice weekly, IP) treatment commenced between weeks 3-6. At the termination of each study (week 8), gross anatomical observations were made of the primary pancreatic tumor and metastatic lesions in the surrounding tissues including the spleen, intestines and liver. The primary pancreatic tumor was weighed and further processed for immunohistochemistry and mRNA expression of fibrotic matrix markers (fibronectin and COLI) and shh signaling (shh and Gli1). Gemcitabine was increasingly less effective when started at later time points, but still reduced the primary tumor weight by 60-70% (30-45 mg/kg) when treatment was started at week 5. M402 was also effective as monotherapy. The addition of M402 to gemcitabine showed only marginally more activity on primary tumor burden; however, metastasis, invasion, and surrounding fibrotic lesions appeared more impacted by the combination treatment than either agent alone. Immunohistochemical and qPCR analyses showed reduced shh and Gli1 with M402 and gemcitabine combination treatment. These results show that M402 can modulate tumor-stroma interactions involved in the desmoplastic response in a murine model of pancreatic cancer. These results provide a rationale for the clinical investigation of M402 as a potential anti-desmoplastic agent in pancreatic cancer patients.<<
Cheers, Tuck |
