Targeting chemoresistant colorectal cancer via systemic administration of a BMP7 variant

Abstract

Despite intense research and clinical efforts, patients affected by advanced colorectal cancer (CRC) have still a poor prognosis. The discovery of colorectal (CR) cancer stem cell (CSC) as the cell compartment responsible for tumor initiation and propagation may provide new opportunities for the development of new therapeutic strategies. Given the reduced sensitivity of CR-CSCs to chemotherapy and the ability of bone morphogenetic proteins (BMP) to promote colonic stem cell differentiation, we aimed to investigate whether an enhanced variant of BMP7 (BMP7v) could sensitize to chemotherapyresistant CRC cells and tumors. Thirty-five primary human cultures enriched in CR-CSCs, including four from chemoresistant metastatic lesions, were used for in vitro studies and to generate CR-CSC-based mouse avatars to evaluate tumor growth and progression upon treatment with BMP7v alone or in combination with standard therapy or PI3K inhibitors. BMP7v treatment promotes CR-CSC differentiation and recapitulates the cell differentiation-related gene expression profile by suppressing Wnt pathway activity and reducing mesenchymal traits and survival of CR-CSCs. Moreover, in CR-CSC-based mouse avatars, BMP7v exerts an antiangiogenic effect and sensitizes tumor cells to standard chemotherapy regardless of the mutational, MSI, and CMS profiles. Of note, tumor harboring PIK3CA mutations were affected to a lower extent by the combination of BMP7v and chemotherapy. However, the addition of a PI3K inhibitor to the BMP7v-based combination potentiates PIK3CA-mutant tumor drug response and reduces the metastatic lesion size. These data suggest that BMP7v treatment may represent a useful antiangiogenic and prodifferentiation agent, which renders CSCs sensitive to both standard and targeted therapies.

PRMT1 inhibition induces differentiation of colon cancer cells

“…Several approaches of differentiation pathway targeting were reported 9 . There are usage of signaling molecules, such as retinoic acid (RA) 7 , cAMP 10 , retinoids 11 , peroxisome proliferator-activated receptor—γ (PPARγ) antagonist 12 , PTPRK-RSPO3 function-blocking antibodies 13 , inhibition of IDH1 in IDH1-mutant tumors 14 , inhibition of aurora kinase 15 , epigenetic modulators of Bromodomain-containing protein 4 (BRD4i) 16 , administration of bone morphogenetic proteins 17 , such as enhanced variant of BMP7 18 and inhibition of histone deacetylase (HDAC). A number of HDAC inhibitors were evaluated in clinical trials and some of them such as vorinostat (SAHA), romidepsin (depsipeptide) and belinostat (PXD-101) have been approved for therapy of blood cancers by the US Food and Drug Administration (FDA) 19 .…”

Hedgehog-GLI signalling promotes chemoresistance through the regulation of ABC transporters in colorectal cancer cells

“…Cells were treated with 10 μM GANT61 (ENZO Lifesciences), and equimolar concentration of Oxaliplatin (Selleckchem) and 5-Fluorouracil (5-FU) (Selleckchem) as described earlier 41 . In detail, to avoid precipitation of the combined Oxaliplatin and 5-FU, we administered 5-FU three hours after Oxaliplatin.…”

Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment

“…In preclinical studies, treatment with WNT/bcatenin inhibitors, iLGK974, Wnt-C59, and cyclosporin A, impaired CSC survival in different cancer types (129)(130)(131). In this context, we have recently demonstrated that the use of a variant of BMP7 with enhanced stability (BMP7v) induced the differentiation of CD44v6 + cells, suppressed Wnt pathway activity and sensitized CSCs to standard and target therapies (132). Recently, we demonstrated that cytokines secreted by CAFs boosted resistance to PI3K/AKT inhibitors in colorectal CSCs and this protective effect was overcome by the triple targeting of Her2, PI3K and MEK (103).…”