Momenta Pharma $MNTA will present two abstracts on it novel heparin-based cancer drug candidate M402 at the AACR cancer research meeting next week. The timeline for an IND submission has been repeatedly delayed, but should occur in 2012.
Abstract Number: 1524
M402, a novel heparan sulfate mimetic, inhibits pancreatic tumor growth and desmoplasia potentially via sonic hedgehog signaling in an orthotopic mouse model
One of the hallmarks of pancreatic ductal adenocarcinoma (PDAC) is extensive desmoplasia in the surrounding tumor microenvironment that prevents delivery of chemotherapeutics (such as gemcitabine). Dysregulation of sonic hedgehog (SHH, a heparin-binding morphogen), has been implicated in pancreatic cancer tumorigenesis. We have rationally designed a heparan sulfate mimetic, M402, that has previously been shown in animal studies to reduce metastatic seeding through disruption of several key heparin-binding growth factors (including FGF2, VEGF, SDF-1α and P-Selectin). 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 secretes SHH and displays a desmoplastic response in vivo. Capan-2 human adenocarcinoma cells (~1x106 cells) were injected into the pancreata of immunodeficient mice (Nu/Nu CD-1). M402 (10-40 mg/kg/day) or saline treatment commenced on Day 4 or 32. 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. Gemcitabine was increasingly less effective when started at later time points, but still reduced the primary tumor weight by 60-70% (at 30-45 mg/kg) when treatment was started at week 5. While the addition of M402 to gemcitabine showed some additive effect on primary tumor burden,metastasis, invasion, and surrounding fibrotic lesions appeared particularly impacted by the combination treatment. M402 was also effective as monotherapy showing a dose-dependent reduction in primary tumor weight and fibrotic lesions. Immunohistochemical and qPCR analyses showed reduced fibrosis and SHH signaling with M402 and gemcitabine combination treatment. These results demonstrate that M402 can modulate tumor-stroma interactions involved in the desmoplastic response in a murine model of pancreatic cancer and provide a rationale for the clinical investigation of M402 as a potential anti-desmoplastic agent in pancreatic cancer therapy.
Abstract Number: 2336
M402, a heparan sulfate mimetic, inhibits tumor revascularization and invasiveness after high-dose taxane treatment in a mouse breast cancer model
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) and other stromal cells, which migrate to the viable tumor rim where they can enhance tumor vascularization, invasion and metastasis. 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. Stromal cells like EPCs are mobilized in response to circulating growth factors and chemokines (VEGFR, FGF, G-CSF, IL-6, SDF1α, 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 tumor vascularization and invasion. Mice bearing orthotopic 4T1 breast carcinoma and treated with a single high dose of docetaxel (40 mg/kg) showed highly vascularized tumor rims by histology and Microfil perfusion followed by microCT (vessel volume of 5.8 ± 4.6 mm3 vs. 0.6 ± 0.3 mm3; vessel surface area of 153.9 ± 65.5 mm2 vs. 21.1 ± 6.7 mm2, respectively) as compared to the saline control group. The tumors also showed a higher rate of invasion through the peritoneal wall as compared to vehicle treated mice (5 of 16 mice vs. 2 of 16 mice, respectively). The effect correlated with mobilization of EPCs and other bone marrow derived stromal cells. Treatment with M402 did not show such a response but rather inhibited the effects of docetaxel when dosed concomitantly for 3-5 days, starting with the docetaxel administration. Analysis of the blood, tumor and bone marrow indicated that M402 prevented the mobilization of progenitor cells from the bone marrow and their recruitment into the tumor microenvironment, likely through disruption of the SDF-1α/CXCR4 axis. Furthermore, we observed synergistic anti-tumor and anti-metastatic activity of M402 with docetaxel in this 4T1 model. In conclusion, the experiments provide a rationale for the clinical investigation of M402 in combination with docetaxel or other agents that induce similar effects.
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