A Multifunctional Therapy Approach for Cancer: Targeting Raf1- Mediated Inhibition of Cell Motility, Growth, and Interaction with the Microenvironment

Abstract

Prostate cancer cells move from their primary site of origin, interact with a distant microenvironment, grow, and thereby cause death. It had heretofore not been possible to selectively inhibit cancer cell motility. Our group has recently shown that inhibition of intracellular activation of Raf1 with the smallmolecule therapeutic KBU2046 permits, for the first time, selective inhibition of cell motility. We hypothesized that simultaneous disruption of multiple distinct functions that drive progression of prostate cancer to induce death would result in advanced disease control. Using a murine orthotopic implantation model of human prostate cancer metastasis, we demonstrate that combined treatment with KBU2046 and docetaxel retains docetaxel's antitumor action, but provides improved inhibition of metastasis, compared with monotherapy. KBU2046 does not interfere with hormone therapy, inclusive of enzalutamide-mediated inhibition of androgen receptor (AR) function and cell growth inhibition, and inclusive of the ability of castration to inhibit LNCaP-AR cell outgrowth in mice. Cell movement is necessary for osteoclast-mediated bone degradation. KBU2046 inhibits Raf1 and its downstream activation of MEK1/2 and ERK1/2 in osteoclasts, inhibiting cytoskeleton rearrangement, resorptive cavity formation, and bone destruction in vitro, with improved effects observed when the bone microenvironment is chemically modified by pretreatment with zoledronic acid. Using a murine cardiac injection model of human prostate cancer bone destruction quantified by CT, KBU2046 plus zoledronic exhibit improved inhibitory efficacy, compared with monotherapy. The combined disruption of pathways that drive cell movement, interaction with bone, and growth constitutes a multifunctional targeting strategy that provides advanced disease control.

Distal gene regulation mediated by non-coding RNAs contributes to germline risk for breast and prostate cancer

“…In prostate tumors, LINC02903 showed significant mediation with the most distal-eQTLs (177 (65,66). The majority of distal-eQTLs mediated by SNHG2 are for RAF1, a therapeutic target for multiple cancers (46). We did not detect any shared ncRNAs or pcGenes across noncancerous and tumor prostate tissue.…”

“…MT4 belongs to the metallothionein family involved in breast cancer carcinogenesis (42, 43), and GPRC6A is a part of the androgen receptor signaling pathway (44, 45). In non-cancerous prostate tissue, we detected large distal mediation effects for genes such as RAF1 , a proto-oncogene (46) and LGR5 , a gene associated with prostatic regeneration and overexpressed in prostate tumors (47). We also detected a number of olfactory receptors ( OR2T1 , OR10G8 , OR10S1 ) with large mediated effects in prostate tumor.…”

“…A majority (22/26) of distal-eQTLs mediated by FBXO30-DT are for OVCH2 , which has been implicated in prostate risk through GWAS (65, 66). The majority of distal-eQTLs mediated by SNHG2 are for RAF1 , a therapeutic target for multiple cancers (46). We did not detect any shared ncRNAs or pcGenes across non-cancerous and tumor prostate tissue.…”

“…In breast tumors, we find that MT4 and GPRC6A have large mediated distal effects; MT4 is a part of the metallothionein family with roles in breast cancer carcinogenesis 35,36 , and GPRC6A is involved in the androgen receptor signaling pathway 37,38 . In non-cancerous prostate tissue, we detect large distal mediation effects for genes such as RAF1, a proto-oncogene 39 , LGR5, a gene associated with prostatic regeneration and overexpressed in prostate tumors 40 , and SAXO2, a microtubule stabilizer that has been targeted for cancer therapies 41,42 . We also detect a number of chemical stimulus and olfactory receptors (OR2T1, OR10G8, OR10S1) with large mediated effects in prostate tumor; olfactory receptors have shown some involvement with prostate cancer progression, though they generally have low expression in prostate tumors 43,44 .…”

Bone‐on‐a‐Chip: Microfluidic Technologies and Microphysiologic Models of Bone Tissue

“…Most studies investigating bone regeneration and cancer mediated bone destruction are conducted using conventional in vitro 2D cell culture systems or in vivo animal models. [ 12–15 ] Conventional cell culture protocols provide the ability to study cell behavior using relatively cheap materials and simple technologies. [ 16 ] However, they lack the ability to replicate the 3D nature of the bone microenvironment, as well as many of the dynamic cell–cell and cell–matrix interactions that are necessary for physiological bone function.…”