Tumor microenvironment: becoming sick of Myc

Several years ago, we described Myc as “the oncogene from hell”, since evidence had just emerged that Myc, aside from being responsible for cell-cycle progression and tumor expansion, was also able to induce genomic instability in culture, wreaking havoc in tumor cells and accelerating tumor progression (Soucek and Evan, Cancer Cell 1:406–408, 2002; Vafa et al., Mol Cell 9:1031–1044, 2002). In this review, we discuss recent publications that expand Myc’s evil armory to include coordination of the crosstalk between tumor and microenvironment. Indeed, endogenous Myc, acting as a client for upstream oncogenic lesions, instructs the tumor stroma, engages a complex inflammatory response and induces angiogenesis, thus allowing the tumor to thrive. This is highly topical in light of the fact that Hanahan and Weinberg have recently redefined the hallmarks of cancer and pointed out that genomic instability and inflammation are essential for both their acquisition and development (Hanahan and Weinberg, Cell 144:646–674, 2011). Myc, it seems, is behind it all

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 in vitro and in vivo using an Omomyc-based mini-protein

The long journey to bring a Myc inhibitor to the clinic

Whitfield and Soucek discuss decades of research and a vast array of strategies that are finally yielding clinical trials for Myc inhibitors in cancer. 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. However, major breakthroughs in the development of Myc inhibitors have arisen in the last couple of years. Notably, the direct Myc inhibitor that we developed has just entered clinical trials. Celebrating this milestone, with this Perspective, we pay homage to the different strategies developed so far against Myc and all of the researchers focused on developing treatments for a target long deemed undruggable

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. Now, much more than a proof of concept, the most characterized Myc inhibitor to date is advancing in its drug development pipeline, pushing Myc inhibition into the clinic

Targeting MYC-driven lymphoma: lessons learned and future directions

B-cell lymphoma; MYCLimfoma de cèl·lules b; MYCLinfoma de células b; MYCMYC 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. In such a context, MYC targeting therapies are of special interest, as MYC withdrawal is expected to result in tumor regression. However, whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet. Even though no MYC inhibitor has received regulatory approval to date, substantial efforts have been made to investigate avenues to render MYC a druggable target. Here, we summarize the different classes of molecules currently under development, which mostly target MYC indirectly in aggressive B-cell lymphomas, paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.Research in our laboratory was supported by the Retos-Colaboración [RTC2019-007067-1] grant from the Spanish Ministry of Economy and Competitiveness. We acknowledge VHIO and the Cellex Foundation for providing research facilities and equipment

eIF4A dependency: the hidden key to unlock KRAS mutant non-small cell lung cancer’s vulnerability

MYC; Non-small cell lung cancerMYC; Càncer de pulmó de cèl·lules no petitesMYC; Cáncer de pulmón de células no pequeñasThe authors received funding support by the “Proyectos de I+D+i en Líneas Estratégicas” (PLEC2021-007959) grant from the Spanish Ministry of Economy and Competitiveness; La Marató TV3 grant [2019429]; and the 2nd BBVA Foundation Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI-II) grant. I.G.L. was supported by a grant from the University Teacher Training Program (FPU), Ministry of Universities (FPU20/04812). Authors from VHIO acknowledge the State Agency for Research (Agencia Estatal de Investigación) the financial support as a Center of Excellence Severo Ochoa (CEX2020-001024-S/AEI/10.13039/501100011033)

Resveratrol derivatives: Synthesis and their biological activities

Resveratrol, a natural compound known especially for its antioxidant properties and protective action, opens the door for both it and its structural derivatives to be considered not only as chemopreventive but also as cancer chemotherapeutic agents. Due to the pharmacokinetic problems of resveratrol that demonstrate its poor bioavailability, the study of new derivatives is of interest. Thus, in this work (E)-stilbenes derived directly from resveratrol and other cyclic analogues containing the benzofuran or indole nucleus have been synthesized. The synthesized compounds have been evaluated for their ability to affect tumor growth in vitro. Compounds 2, 3, 4 and 5 have shown cytotoxicity in human colon cancer (HT-29) and human pancreatic adenocarcinoma cells (MIA PaCa-2) higher than those of (E)-resveratrol. The indolic derivative 13, a cyclic analog of resveratrol, has shown in vitro cytotoxic activity 8 times higher than resveratrol against HT-29 cancer cells. The cyclic derivatives 8, 9 and 12 showed a high inhibition of cell growth in HCT-116 (KRas mutant) at 20 μM, while 13 shows moderate antiangiogenesis activity at 10 μM

MYC: there is more to it than cancer

MYC; Non-oncological diseases; Transcription factorMYC; Enfermedades no oncológicas; Factor de transcripcionMYC; Malalties no oncològiques; Factor de transcripcióMYC 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. In this context, an abundance of reviews describes strategies for potentially targeting MYC in the oncology field. However, its multiple roles in different aspects of cellular biology suggest that it may also play a role in many additional diseases, and other publications are indeed linking MYC to pathologies beyond cancer. Here, we review these physiological functions and the current literature linking MYC to non-oncological diseases. The intense efforts towards developing MYC inhibitors as a cancer therapy will potentially have huge implications for the treatment of other diseases. In addition, with a complementary approach, we discuss some diseases and conditions where MYC appears to play a protective role and hence its increased expression or activation could be therapeutic.The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Authors acknowledge funding support from the Spanish Ministry of Science and Innovation (Fondo de Investigación en Salud [FIS] PI19/01277, the State Agency for Research (Agencia Estatal de Investigación) as a Center of Excellence Severo Ochoa (CEX 2020-001024-S/AEI/10.13039/501100011033), the Generalitat de Catalunya (AGAUR 2021/SGR 01509), and the FERO foundation

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

MYC; Oncogenes; CancerMYC; Oncogens; CàncerMYC; Oncogenes; CáncerRAS 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. Due to their frequent alteration and role in tumorigenesis, MYC and RAS emerge as highly appealing targets in cancer therapy. However, due to their complex nature, both oncogenes have been long considered “undruggable” and, until recently, no drugs directly targeting them had reached the clinic. This review aims to shed light on their complex partnership, with special attention to their active collaboration in fostering an immunosuppressive milieu and driving immunotherapeutic resistance in cancer. Within this review, we also present an update on the different inhibitors targeting RAS and MYC currently undergoing clinical trials, along with their clinical outcomes and the different combination strategies being explored to overcome drug resistance. This recent clinical development suggests a paradigm shift in the long-standing belief of RAS and MYC “undruggability”, hinting at a new era in their therapeutic targeting.The authors received funding support by the “Proyectos de I+D+i enLíneas Estratégicas” (PLEC2021-007959) grant from the Spanish Ministry of Economy and Competitiveness; La Marató TV3 grant (2019429); the Spanish Ministry of Science and Innovation and European Union through the NextGenerationEU program, in the context of the Plan de Recuperacion, Transformacion y Resiliencia (RETOS; CPP2022-009808); a European Research Council (ERC) Advanced Grant (101142260); and the 2nd BBVA Foundation Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI-II) grant. I.G.-L. was supported by a grant from the University Teacher Training Program (FPU), Ministry of Universities (FPU20/04812). Authors from VHIO acknowledge the State Agency for Research (Agencia Estatal de Investigación) the financial support as a Center of Excellence Severo Ochoa (CEX2020-001024-S/AEI/ 10.13039/501100011033)

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology