Our Science
Carcinoma-associated fibroblasts (CAFs) play integral roles in virtually all hallmarks of cancer including promoting cancer growth and metastasis, spurring angiogenesis, suppressing anti-tumor immunity and fostering chemo-resistance. These pro-tumorigenic activities are driven by secreted CAF factors that can profoundly influence the biology of cancer and host cells in the tumor microenvironment. The discovery and therapeutic targeting of these symbiotic factors to defeat cancer lies at the heart of Stellanova’s science and mission. Our discovery platform integrates advanced computational biology, including single cell analyses, sophisticated cell biological functional assays enabled genetic engineering, and a state-of-the-art antibody discovery and development platform.
In pancreatic cancer, the stellate cell CAFs secrete DKK3 (1) which has multiple effects on the tumor microenvironment. DKK3 promotes cancer cell growth and metastasis (2), inhibits cancer response to chemotherapy, stimulates other CAF activity (3), and inhibits killer T cells (4).
Blocking DKK3 with a specific antibody (1) inhibits cancer (2) and stellate cell activity (3) to reduce tumor progression. This also allows T cells to enter the tumor (4) which now become responsive to immunotherapy, resulting in significant improvement in survival in animal models.
Our lead candidate is an antibody targeting the factor DKK3 which functions to promote cancer cell therapeutic resistance, metastases, and immune suppression. Our anti-DKK3 antibody shows unprecedented anti-tumor activity in pancreas cancer models, alone and in combination with checkpoint blockade inhibitors, as well as anti-tumor activity in triple negative breast cancer models.
Targeting the Tumor Microenvironment for Cancer Therapy
Pancreatic adenocarcinoma is a lethal tumor that is resistant to current treatments. It is even impervious to immunotherapy, one of the most advanced weapons in the war on cancer. Pancreatic cancer surrounds itself with an immune system-proof shield of co-opted bystander stellate cells, a specific type of cancer-associated fibroblasts (CAFs). The stellate cells also protect cancer against chemotherapy. Stellanova’s founders discovered a way to strip cancer of its protective stellate shield and make it vulnerable to the immune system’s attacks as well as improve the potency of chemotherapy. Stellanova’s lead antibody drug showed significant improvement in survival in otherwise lethal pre-clinical mouse models of pancreatic cancer and in combination with immunotherapy, this antibody has produced complete cures.
References:
Science Translational Medicine
2018 Oct 24;10(464):eaat3487. doi: 10.1126/scitranslmed.aat3487
Suppression of stromal-derived Dickkopf-3 (DKK3) inhibits tumor progression and prolongs survival in pancreatic ductal adenocarcinom
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Nature Reviews Drug Discovery
2019 Feb;18(2):99-115. doi: 10.1038/s41573-018-0004-1
Turning foes to friends: targeting cancer-associated fibroblasts
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Cancer Discovery
2021 May;11(5):1067-1081. doi: 10.1158/2159-8290.CD-20-1211. Epub 2021 Jan 27
Metabolic Codependencies in the Tumor Microenvironm
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Cancer Cell
2012 Mar 20;21(3):309-22. doi: 10.1016/j.ccr.2012.02.022
Accessories to the crime: functions of cells recruited to the tumor microenvironment
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