Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors.

The redirection of T lymphocytes against tumor-associated or tumor-specific antigens, using bispecific antibodies or chimeric antigen receptors (CAR), has shown therapeutic success against certain hematological malignancies. However, this strategy has not been effective against solid tumors. Here, we describe the development of CAR T cells targeting p95HER2, a tumor-specific antigen found in HER2-amplified solid tumors.

MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer.

RAS and MYC rank amongst the most commonly altered oncogenes in cancer, with RAS being the most frequently mutated and MYC the most amplified. The cooperative interplay between RAS and MYC constitutes a complex and multifaceted phenomenon, profoundly influencing tumor development. Together and individually, these two oncogenes regulate most, if not all, hallmarks of cancer, including cell death escape, replicative immortality, tumor-associated angiogenesis, cell invasion and metastasis, metabolic adaptation, and immune evasion.

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: there is more to it than cancer.

MYC is a pleiotropic transcription factor involved in multiple cellular processes. While its mechanism of action and targets are not completely elucidated, it has a fundamental role in cellular proliferation, differentiation, metabolism, ribogenesis, and bone and vascular development. Over 4 decades of research and some 10,000 publications linking it to tumorigenesis (by searching PubMed for "MYC oncogene") have led to MYC becoming a most-wanted target for the treatment of cancer, where many of MYC's physiological functions become co-opted for tumour initiation and maintenance.

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.

MYC inhibitors in multiple myeloma.

The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified. Since then, over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation, especially in hematologic diseases. Indeed, some of the earliest connections among the higher expression of proto-oncogenes (such as ), genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma, chronic myeloid leukemia and mouse plasmacytomas.

Frequent mutations of FBXO11 highlight BCL6 as a therapeutic target in Burkitt lymphoma.

The expression of BCL6 in B-cell lymphoma can be deregulated by chromosomal translocations, somatic mutations in the promoter regulatory regions, or reduced proteasome-mediated degradation. FBXO11 was recently identified as a ubiquitin ligase that is involved in the degradation of BCL6, and it is frequently inactivated in lymphoma or other tumors. Here, we show that FBXO11 mutations are found in 23% of patients with Burkitt lymphoma (BL).

The long journey to bring a Myc inhibitor to the clinic.

The oncogene Myc is deregulated in the majority of human tumors and drives numerous hallmarks of cancer. Despite its indisputable role in cancer development and maintenance, Myc is still undrugged. Developing a clinical inhibitor for Myc has been particularly challenging owing to its intrinsically disordered nature and lack of a binding pocket, coupled with concerns regarding potentially deleterious side effects in normal proliferating tissues.

An "-omycs" Toolbox to Work with MYC.

The MYC transcription factor coordinates a wide range of intra- and extracellular processes associated with tissue proliferation and regeneration. While these processes are typically tightly regulated in physiological conditions, they become deregulated in cancer, where MYC is oncogenically activated.The last decade has seen MYC progress from a renowned undruggable target to a hot topic in the cancer therapy field, as proof emerged from mouse models that its inhibition constitutes an effective and broadly applicable approach to fight cancer.

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.

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc.

First designed and published in 1998 as a laboratory tool to study Myc perturbation, Omomyc has come a long way in the past 22 years. This dominant negative has contributed to our understanding of Myc biology when expressed, first, in normal and cancer cells, and later in genetically-engineered mice, and has shown remarkable anti-cancer properties in a wide range of tumor types. The recently described therapeutic effect of purified Omomyc mini-protein-following the surprising discovery of its cell-penetrating capacity-constitutes a paradigm shift.

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.

MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype.

The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this -driven PDAC switch is completely and immediately reversible: deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells.

Epigenetic Repression in Tumor-Associated Fibroblasts Impairs Fibrosis and Response to the Antifibrotic Drug Nintedanib in Lung Squamous Cell Carcinoma.

The tumor-promoting fibrotic stroma rich in tumor-associated fibroblasts (TAF) is drawing increased therapeutic attention. Intriguingly, a trial with the antifibrotic drug nintedanib in non-small cell lung cancer reported clinical benefits in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC), even though the stroma is fibrotic in both histotypes. Likewise, we reported that nintedanib inhibited the tumor-promoting fibrotic phenotype of TAFs selectively in ADC.

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.