EV20/Omomyc: A novel dual MYC/HER3 targeting immunoconjugate.

MYC is one of the most important therapeutic targets in human cancer. Many attempts have been made to develop small molecules that could be used to curb its activity in patients, but most failed to identify a suitable direct inhibitor. After years of preclinical characterization, a tissue-penetrating peptide MYC inhibitor, called Omomyc, has been recently successfully used in a Phase I dose escalation study in late-stage, all-comers solid tumour patients.

MYC targeting by OMO-103 in solid tumors: a phase 1 trial.

Among the 'most wanted' targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein.

Targeting MYC-driven lymphoma: lessons learned and future directions.

MYC plays a central role in tumorigenesis by orchestrating cell proliferation, growth and survival, among other transformation mechanisms. In particular, MYC has often been associated with lymphomagenesis. In fact, MYC overexpressing lymphomas such as high-grade B-cell lymphoma (HGBL) and double expressor diffuse large B-cell lymphomas (DLBCL), are considered addicted to MYC.

Reducing MYC's transcriptional footprint unveils a good prognostic gene signature in melanoma.

MYC's key role in oncogenesis and tumor progression has long been established for most human cancers. In melanoma, its deregulated activity by amplification of 8q24 chromosome or by upstream signaling coming from activating mutations in the RAS/RAF/MAPK pathway-the most predominantly mutated pathway in this disease-turns MYC into not only a driver but also a facilitator of melanoma progression, with documented effects leading to an aggressive clinical course and resistance to targeted therapy. Here, by making use of Omomyc, the most characterized MYC inhibitor to date that has just successfully completed a phase I clinical trial, we show for the first time that MYC inhibition in melanoma induces remarkable transcriptional modulation, resulting in severely compromised tumor growth and a clear abrogation of metastatic capacity independently of the driver mutation.

MYC Inhibition Halts Metastatic Breast Cancer Progression by Blocking Growth, Invasion, and Seeding.

Unlabelled: MYC's role in promoting tumorigenesis is beyond doubt, but its function in the metastatic process is still controversial. Omomyc is a MYC dominant negative that has shown potent antitumor activity in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, by impacting on several of the hallmarks of cancer. However, its therapeutic efficacy against metastasis has not been elucidated yet.

Pharmacokinetic Analysis of Omomyc Shows Lasting Structural Integrity and Long Terminal Half-Life in Tumor Tissue.

MYC is an oncoprotein causally involved in the majority of human cancers and a most wanted target for cancer treatment. Omomyc is the best-characterized MYC dominant negative to date. In the last years, it has been developed into a therapeutic miniprotein for solid tumor treatment and recently reached clinical stage.

Integrated requirement of non-specific and sequence-specific DNA binding in Myc-driven transcription.

Eukaryotic transcription factors recognize specific DNA sequence motifs, but are also endowed with generic, non-specific DNA-binding activity. How these binding modes are integrated to determine select transcriptional outputs remains unresolved. We addressed this question by site-directed mutagenesis of the Myc transcription factor.

The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets.

The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and β-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation.

Structural and Biophysical Insights into the Function of the Intrinsically Disordered Myc Oncoprotein.

Myc is a transcription factor driving growth and proliferation of cells and involved in the majority of human tumors. Despite a huge body of literature on this critical oncogene, our understanding of the exact molecular determinants and mechanisms that underlie its function is still surprisingly limited. Indubitably though, its crucial and non-redundant role in cancer biology makes it an attractive target.

MYC, MYCL, and MYCN as therapeutic targets in lung cancer.

: Lung cancer is the leading cause of cancer-related mortality globally. Despite recent advances with personalized therapies and immunotherapy, the prognosis remains dire and recurrence is frequent. Myc is an oncogene deregulated in human cancers, including lung cancer, where it supports tumorigenic processes and progression.

Targeting Antitumoral Proteins to Breast Cancer by Local Administration of Functional Inclusion Bodies.

Two structurally and functionally unrelated proteins, namely Omomyc and p31, are engineered as CD44-targeted inclusion bodies produced in recombinant bacteria. In this unusual particulate form, both types of protein materials selectively penetrate and kill CD44 tumor cells in culture, and upon local administration, promote destruction of tumoral tissue in orthotropic mouse models of human breast cancer. These findings support the concept of bacterial inclusion bodies as versatile protein materials suitable for application in chronic diseases that, like cancer, can benefit from a local slow release of therapeutic proteins.

Finding MYCure.

Inhibiting the nuclear protein MYC involved in the majority of human cancers has long been considered an impossible mission and several technical challenges have discouraged the development of MYC inhibitory strategies. Nevertheless, in our recent publication in Science Translational Medicine "Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy", we demonstrate for the first time the feasibility of pharmacological MYC inhibition and using an Omomyc-based mini-protein.

Bioactive cell penetrating peptides and proteins in cancer: a bright future ahead.

Peptides and proteins bear an extraordinary therapeutic potential to effectively and selectively target many components of cells currently considered undruggable. However, their intracellular delivery remains a critical challenge. Cell penetrating peptides and protein domains (CPPs) can be employed to translocate therapeutic polypeptides through the cellular membrane.

Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy.

Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo.

BET inhibition is an effective approach against KRAS-driven PDAC and NSCLC.

Effectively treating KRAS-driven tumors remains an unsolved challenge. The inhibition of downstream signaling effectors is a way of overcoming the issue of direct targeting of mutant KRAS, which has shown limited efficacy so far. Bromodomain and Extra-Terminal (BET) protein inhibition has displayed anti-tumor activity in a wide range of cancers, including KRAS-driven malignancies.

Strategies to Inhibit Myc and Their Clinical Applicability.

Myc is an oncogene deregulated in most-perhaps all-human cancers. Each Myc family member, c-, L-, and N-Myc, has been connected to tumor progression and maintenance. Myc is recognized as a "most wanted" target for cancer therapy, but has for many years been considered undruggable, mainly due to its nuclear localization, lack of a defined ligand binding site, and physiological function essential to the maintenance of normal tissues.

Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal fibroinflammatory reaction that is a major obstacle to effective therapy. The desmoplastic stroma comprises many inflammatory cells, in particular mast cells as key components of the PDAC microenvironment, and such infiltration correlates with poor patient outcome. Indeed, it has been hypothesized that stromal ablation is critical to improve clinical response in patients with PDAC.

Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis.

Gliomas are the most common primary tumours affecting the adult central nervous system and respond poorly to standard therapy. Myc is causally implicated in most human tumours and the majority of glioblastomas have elevated Myc levels. Using the Myc dominant negative Omomyc, we previously showed that Myc inhibition is a promising strategy for cancer therapy.

Methods for the expression, purification, preparation, and biophysical characterization of constructs of the c-Myc and Max b-HLH-LZs.

Specific heterodimerization and DNA binding by the b-HLH-LZ transcription factors c-Myc and Max is central to the activation and repression activities of c-Myc that lead to cell growth, proliferation, and tumorigenesis (Adhikary and Eilers, Nat Rev Mol Cell Biol 6:635-645, 2005; Eilers and Eisenman, Genes Dev 22:2755-2766, 2008; Grandori et al., Annu Rev Cell Dev Biol 16:653-699, 2000; Whitfield and Soucek, Cell Mol Life Sci 69:931-934, 2011). Although many c-Myc-interacting partner proteins are known to interact through their HLH domain (Adhikary and Eilers, Nat Rev Mol Cell Biol 6:635-645, 2005), current knowledge regarding the structure and the determinants of molecular recognition of these complexes is still very limited.

Critical hydrogen bond formation for activation of the angiotensin II type 1 receptor.

G protein-coupled receptors contain selectively important residues that play central roles in the conformational changes that occur during receptor activation. Asparagine 111 (N111(3.35)) is such a residue within the angiotensin II type 1 (AT(1)) receptor.

The abundance and diversity of legume-nodulating rhizobia in 28-year-old plantations of tropical, subtropical, and exotic tree species: a case study from the Forest Reserve of Bandia, Senegal.

Several fast-growing and multipurpose tree species have been widely used in West Africa to both reverse the tendency of land degradation and restore soil productivity. Although beneficial effects have been reported on soil stabilization, there still remains a lack of information about their impact on soil microorganisms. Our investigation has been carried out in exotic and native tree plantations of 28 years and aimed to survey and compare the abundance and genetic diversity of natural legume-nodulating rhizobia (LNR).

New structural determinants for c-Myc specific heterodimerization with Max and development of a novel homodimeric c-Myc b-HLH-LZ.

c-Myc must heterodimerize with Max to accomplish its functions as a transcription factor. This specific heterodimerization occurs through the b-HLH-LZ (basic region, helix 1-loop-helix 2-leucine zipper) domains. In fact, many studies have shown that the c-Myc b-HLH-LZ (c-Myc'SH) preferentially forms a heterodimer with the Max b-HLH-LZ (Max'SH).

Identification of transmembrane domain 6 & 7 residues that contribute to the binding pocket of the urotensin II receptor.

Urotensin II (U-II), a cyclic undecapeptide, is the natural ligand of the urotensin II (UT) receptor, a G protein-coupled receptor. In the present study, we used the substituted-cysteine accessibility method to identify specific residues in transmembrane domains (TMDs) six and seven of the rat urotensin II receptor (rUT) that contribute to the formation of the binding pocket of the receptor. Each residue in the R256(6.

Photolabelling the urotensin II receptor reveals distinct agonist- and partial-agonist-binding sites.

The mechanism by which GPCRs (G-protein-coupled receptors) undergo activation is believed to involve conformational changes following agonist binding. We have used photoaffinity labelling to identify domains within GPCRs that make contact with various photoreactive ligands in order to better understand the activation mechanism. Here, a series of four agonist {[Bpa1]U-II (Bpa is p-benzoyl-L-phenylalanine), [Bpa2]U-II, [Bpa3]U-II and [Bpa4]U-II} and three partial agonist {[Bpa1Pen5D-Trp7Orn8]U-II (Pen is penicillamine), [Bpa2Pen5D-Trp7Orn8]U-II and [Pen5Bpa6D-Trp7Orn8]U-II} photoreactive urotensin II (U-II) analogues were used to identify ligand-binding sites on the UT receptor (U-II receptor).