CHD1L Inhibitor OTI-611 Synergizes with Chemotherapy to Enhance Antitumor Efficacy and Prolong Survival in Colorectal Cancer Mouse Models.

Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer. It is universally treated with a combination of the DNA damaging chemotherapy drugs irinotecan, 5-Fluorouracil (5-FU), and oxaliplatin. is a novel oncogene that plays critical roles in chromatin remodeling and DNA damage repair, as well as the regulation of malignant gene expression.

CHD1L Regulates Cell Survival in Breast Cancer and Its Inhibition by OTI-611 Impedes the DNA Damage Response and Induces PARthanatos.

The Chromodomain helicase DNA-binding protein 1-like (CHD1L) is a nucleosome remodeling enzyme, which plays a key role in chromatin relaxation during the DNA damage response. Genome editing has shown that deletion of CHD1L sensitizes cells to PARPi, but the effect of its pharmacological inhibition has not been defined. Triple-negative breast cancer SUM149PT, HCC1937, and MDA-MB-231 cells were used to assess the mechanism of action of the CHD1Li OTI-611.

HTS discovery of PARP1-HPF1 complex inhibitors in cancer.

PARP1/2 inhibitors (PARPi) are effective clinically used drugs for the treatment of cancers with BRCA deficiencies. PARPi have had limited success and applicability beyond BRCA deficient cancers, and their effect is diminished by resistance mechanisms. The recent discovery of Histone PARylation Factor (HPF1) and the role it plays in the PARylation reaction by forming a shared active site with PARP1 raises the possibility that novel inhibitors that target the PARP1-HPF1 complex can be identified.

Surfaceome Profiling of Cell Lines and Patient-Derived Xenografts Confirm FGFR4, NCAM1, CD276, and Highlight AGRL2, JAM3, and L1CAM as Surface Targets for Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The prognosis for patients with high-grade and metastatic disease is still very poor, and survivors are burdened with long-lasting side effects. Therefore, more effective and less toxic therapies are needed.

GSDMD-dependent pyroptotic induction by a multivalent CXCR4-targeted nanotoxin blocks colorectal cancer metastases.

Colorectal cancer (CRC) remains the third cause of cancer-related mortality in Western countries, metastases are the main cause of death. CRC treatment remains limited by systemic toxicity and chemotherapy resistance. Therefore, nanoparticle-mediated delivery of cytotoxic agents selectively to cancer cells represents an efficient strategy to increase the therapeutic index and overcome drug resistance.

A refined cocktailing of pro-apoptotic nanoparticles boosts anti-tumor activity.

A functional 29 amino acid-segment of the helix α5 from the human BAX protein has been engineered for production in recombinant bacteria as self-assembling, GFP-containing fluorescent nanoparticles, which are targeted to the tumoral marker CXCR4. These nanoparticles, of around 34 nm in diameter, show a moderate tumor biodistribution and limited antitumoral effect when systemically administered to mouse models of human CXCR4 colorectal cancer (at 300 μg dose). However, if such BAX nanoparticles are co-administered in cocktail with equivalent nanoparticulate versions of BAK and PUMA proteins at the same total protein dose (300 μg), protein biodistribution and stability in tumor is largely improved, as determined by fluorescence profiles.

Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci.

Functional amyloids produced in bacteria as nanoscale inclusion bodies are intriguing but poorly explored protein materials with wide therapeutic potential. Since they release functional polypeptides under physiological conditions, these materials can be potentially tailored as mimetic of secretory granules for slow systemic delivery of smart protein drugs. To explore this possibility, bacterial inclusion bodies formed by a self-assembled, tumor-targeted Pseudomonas exotoxin (PE24) are administered subcutaneously in mouse models of human metastatic colorectal cancer, for sustained secretion of tumor-targeted therapeutic nanoparticles.

Collaborative membrane activity and receptor-dependent tumor cell targeting for precise nanoparticle delivery in CXCR4 colorectal cancer.

By the appropriate selection of functional peptides and proper accommodation sites, we have generated a set of multifunctional proteins that combine selectivity for CXCR4 cell binding and relevant endosomal escape capabilities linked to the viral peptide HA2. In particular, the construct T22-GFP-HA2-H6 forms nanoparticles that upon administration in mouse models of human, CXCR4 colorectal cancer, accumulates in primary tumor at levels significantly higher than the parental T22-GFP-H6 HA2-lacking version. The in vivo application of a CXCR4 antagonist has confirmed the prevalence of the CXCR4 tumor tissue selectivity over unspecific cell penetration, upon systemic administration of the material.

Selective depletion of metastatic stem cells as therapy for human colorectal cancer.

Selective elimination of metastatic stem cells (MetSCs) promises to block metastatic dissemination. Colorectal cancer (CRC) cells overexpressing CXCR4 display trafficking functions and metastasis-initiating capacity. We assessed the antimetastatic activity of a nanoconjugate (T22-GFP-H6-FdU) that selectively delivers Floxuridine to CXCR4 cells.

Release of targeted protein nanoparticles from functional bacterial amyloids: A death star-like approach.

Sustained release of drug delivery systems (DDS) has the capacity to increase cancer treatment efficiency in terms of drug dosage reduction and subsequent decrease of deleterious side effects. In this regard, many biomaterials are being investigated but none offers morphometric and functional plasticity and versatility comparable to protein-based nanoparticles (pNPs). Here we describe a new DDS by which pNPs are fabricated as bacterial inclusion bodies (IB), that can be easily isolated, subcutaneously injected and used as reservoirs for the sustained release of targeted pNPs.

Self-assembling toxin-based nanoparticles as self-delivered antitumoral drugs.

Loading capacity and drug leakage from vehicles during circulation in blood is a major concern when developing nanoparticle-based cell-targeted cytotoxics. To circumvent this potential issue it would be convenient the engineering of drugs as self-delivered nanoscale entities, devoid of any heterologous carriers. In this context, we have here engineered potent protein toxins, namely segments of the diphtheria toxin and the Pseudomonas aeruginosa exotoxin as self-assembling, self-delivered therapeutic materials targeted to CXCR4 cancer stem cells.

Cancer-specific uptake of a liganded protein nanocarrier targeting aggressive CXCR4 colorectal cancer models.

Unliganded drug-nanoconjugates accumulate passively in the tumor whereas liganded nanoconjugates promote drug internalization in tumor cells via endocytosis and increase antitumor efficacy. Whether or not tumor cell internalization associates with enhanced tumor uptake is still under debate. We here compared tumor uptake of T22-GFP-H6, a liganded protein carrier targeting the CXCR4 receptor, and the unliganded GFP-H6 carrier in subcutaneous and metastatic colorectal cancer models.