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- Title
Humanized anti-DEspR IgG4<sup>S228P</sup> antibody increases overall survival in a pancreatic cancer stem cell-xenograft peritoneal carcinomatosis rat<sup>nu/nu</sup> model.
- Authors
Gromisch, Christopher M.; Tan, Glaiza L. A.; Pasion, Khristine Amber; Moran, Ann-Marie; Gromisch, Matthew S.; Grinstaff, Mark W.; Carr, Francis J.; Herrera, Victoria L. M.; Ruiz-Opazo, Nelson
- Abstract
<bold>Background: </bold>Pancreatic peritoneal carcinomatosis (PPC), with the worst median overall-survival (mOS), epitomizes the incurability of metastatic cancer. Cancer stem cells (CSCs) underpin this incurability. However, inhibitors of CSC-stemness fail to increase mOS in cancer patients despite preclinical tumor-reduction. This shortfall reinforces that preclinical efficacy should be defined by increased mOS in the presence of cancer comorbidities, CSC-heterogeneity and plasticity. The primary objectives of this study are: to test the dual endothelin-1/signal peptide receptor, DEspR, as a nodal therapeutic target in PPC, given DEspR induction in anoikis-resistant pancreatic CSCs, and to validate humanized anti-DEspR antibody, hu-6g8, as a potential therapeutic for PPC.<bold>Methods: </bold>We used heterogeneous pools of CSCs selected for anoikis resistance from reprogrammed Panc1 and MiaPaCa2 tumor cells (TCs), and adherent TCs reprogrammed from CSCs (cscTCs). We used multiple anti-DEspR blocking antibodies (mAbs) with different epitopes, and a humanized anti-DEspR recombinant mAb cross-reactive in rodents and humans, to test DEspR inhibition effects. We measured DEspR-inhibition efficacy on multiple prometastatic CSC-functions in vitro, and on tumorigenesis and overall survival in a CSC-derived xenograft (CDX) nude rat model of PPC with comorbidities.<bold>Results: </bold>Here we show that DEspR, a stress-survival receptor, is present on subsets of PDAC Panc1-TCs, TC-derived CSCs, and CSC-differentiated TCs (cscTCs), and that DESpR-inhibition decreases apoptosis-resistance and pro-metastatic mesenchymal functions of CSCs and cscTCs in vitro. We resolve the DNA-sequence/protein-function discordance by confirming ADAR1-RNA editing-dependent DEspR-protein expression in Panc1 and MiaPaCa2 TCs. To advance DEspR-inhibition as a nodal therapeutic approach for PPC, we developed and show improved functionality of a recombinant, humanized anti-DEspR IgG4S228P antibody, hu-6g8, over murine precursor anti-DEspR mabs. Hu-6g8 internalizes and translocates to the nucleus colocalized with cyto-nuclear shuttling galectins-1/3, and induces apoptotic cell changes. DEspR-inhibition blocks transperitoneal dissemination and progression to peritoneal carcinomatosis of heterogeneous DEspR±/CD133 ± Panc1-derived CSCs in xenografted nude rats, improving mOS without chemotherapy-like adverse effects. Lastly, we show DEspR expression in Stage II-IV primary and invasive TCs in the stroma in PDAC-patient tumor arrays.<bold>Conclusion: </bold>Collectively, the data support humanized anti-DEspR hu-6g8 as a potential targeted antibody-therapeutic with promising efficacy, safety and prevalence profiles for PPC patients.
- Subjects
PERITONEAL cancer; PANCREATIC cancer; CANCER stem cells; PEPTIDE receptors; IMMUNOGLOBULINS; PANCREATIC tumors; BIOLOGICAL models; IMMUNOHISTOCHEMISTRY; ANIMAL experimentation; MONOCLONAL antibodies; CELL receptors; APOPTOSIS; NEOPLASTIC cell transformation; CELL physiology; PERITONEUM tumors; RATS; CELL motility; STEM cells; IMMUNOPHENOTYPING; CELL lines; DRUG resistance in cancer cells; METABOLISM
- Publication
BMC Cancer, 2021, Vol 21, Issue 1, p1
- ISSN
1471-2407
- Publication type
journal article
- DOI
10.1186/s12885-021-08107-w