Saturday, April 19, 2014

Targeting Integrin A6 Stimulates Curative-type Bone Metastasis Lesions in a Xenograft Model


This an article I edited and for which I did some research (discovering articles, not in the lab). I believe there are two important pieces here, one is the effects of an antibody on bone remodeling that captures and contains metastasized prostate cancer. Most prostate cancers that become lethal become lethal through metastasis. If we can stop the metastasis even after it has occurred, we can save a lot of lives. This discovery points toward that possibility.

The other innovation here is the ability to image the bone lesions of cancer in the same animal over time (interventional radiologist Dr. Gerald Pond made this happen). Traditionally, when an animal was imaged at various stages of the trial, it was killed. So the imaging at each stage was a different animal, even though these subjects are genetically cloned, there are still individual differences. By imaging the same animal(s) over the length of the trial, we get a better and more coherent narrative of the anitbody's action in each subject.

Here is the abstract for the article, which is behind a paywall, unfortunately.

Full Citation:
Landowski, TH, Gard, J, Pond, E, Pond, GD, Nagle, RB, Geffre, CP, and Cress, AE. (2014, Apr 16). Targeting Integrin A6 stimulates curative-type bone metastasis lesions in a xenograft model. Molecular Cancer Therapeutics; Published OnlineFirst: doi:10.1158/1535-7163.MCT-13-0962

Targeting Integrin A6 stimulates curative-type bone metastasis lesions in a xenograft model


Terry H Landowski, Jaime Gard, Erika Pond, Gerald D Pond, Raymond B Nagle, Christopher P Geffre, and Anne E Cress

Arizona Cancer Center, University of Arizona

Corresponding Author:
Anne E Cress, Cellular and Molecular Medicine, University of Arizona, 1515 N. Campbell Ave., Tucson, Arizona, 85724, United States cress@email.arizona.edu

Abstract

Laminin binding integrin receptors are key mediators of epithelial cell migration and tumor metastasis. Recent studies have demonstrated a role for the alpha 6 integrin (ITGA6/CD49f) in maintaining stem cell compartments within normal bone marrow and in residency of tumors metastatic to bone. In this study, we tested a function-blocking antibody specific for ITGA6, called J8H, to determine if pre-existing cancer lesions in bone could be slowed and/or animal survival improved. Human prostate tumors were established by intracardiac injection into male severe combined immunodeficient (SCID) mice and treatment with J8H antibody was initiated after one week. Tumor progression was monitored by micro computed tomography (CT) imaging of skeletal lesions. Animals that received weekly injections of the anti-ITGA6 antibody showed radiographic progression in only 40% of osseous tumors (femur or tibia), compared to control animals, where 80% of the lesions (femur or tibia) showed progression at 5 weeks. Kaplan-Meier survival analysis demonstrated a significant survival advantage for J8H-treated animals. Unexpectedly, CT image analysis revealed an increased proportion of bone lesions displaying a sclerotic rim of new bone formation, encapsulating the arrested lytic lesions in animals that received the anti-ITGA6 antibody treatment. Histopathology of the sclerotic lesions demonstrated well-circumscribed tumor within bone, surrounded by fibrosis. These data suggest that systemic targeting of the ITGA6-dependent function of established tumors in bone may offer a non-cytotoxic approach to arrest the osteolytic progression of metastatic prostate cancer, thereby providing a new therapeutic strategy for advanced disease.
  • Received November 15, 2013.
  • Revision received March 6, 2014.
  • Accepted April 2, 2014.
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