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. By reducing MYC's transcriptional footprint in melanoma, Omomyc elicits gene expression profiles remarkably similar to those of patients with good prognosis, underlining the therapeutic potential that such an approach could eventually have in the clinic in this dismal disease.

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. However, since the in vivo stability of therapeutic proteins, especially within the tumor vicinity, can be affected by proteolytic degradation, the perception of Omomyc as a valid therapeutic agent has been often questioned. In this study, we used a mass spectrometry approach to evaluate the stability of Omomyc in tumor biopsies from murine xenografts following its intravenous administration. Our data strongly support that the integrity of the functional domains of Omomyc (DNA binding and dimerization region) remains preserved in the tumor tissue for at least 72 hours following administration and that the protein shows superior pharmacokinetics in the tumor compartment compared with blood serum.

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 ß-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. Together, our results indicate that the Wnt signaling receptor Fzd9 is essential for Myc-induced tumorigenesis in pancreatic islets.

Carcinoma papilar de tiroides, variante de células altas: reporte de caso / Papillary thyroid carcinoma, high cell variant: case report

El carcinoma papilar de tiroides variante de células altas, descrito en 1976 por Hawk y Hazard, representa el 1% de los carcinomas diferenciados, siendo más agresivo e invasivo que la forma clásica y 80% de los casos se asocia con mutación B-RAF. Se presenta el caso de una mujer de 49 años con tumoración dolorosa en cara anterolateral de cuello, que tuvo un crecimiento rápido, disfonía y lateralización del cuello a izquierda. En la ecografía de tiroides se vio en el lóbulo derecho un voluminoso nódulo mixto, predominantemente sólido, hipoecogénico, con micro calcificaciones, sin separación del plano graso con los músculos infra hioideos. Se realizó punción con aguja fina que resultó Bethesda VI. En valoración pre quirúrgico se encontró la parálisis de cuerda vocal derecha. Se realizó tiroidectomía total con vaciamiento central y lateral derecho. El estudio anatomo-patológico reportó un carcinoma papilar de tiroides variante de células altas de 33 x 40 x 27 mm en lóbulo derecho que contacta con la tinta china, evade la cápsula y presenta invasión perineural. Ocho ganglios de 18 analizados fueron metastásicos en el compartimento VI. Posteriormente se realizó rastreo corporal total con una dosis mínima de I131 y luego se administró 150 mCi de I131. El carcinoma papilar de tiroides, variante de células altas puede presentarse inicialmente con el compromiso locorregional y su correcto diagnóstico tiene implicancia en el pronóstico y su manejo terapéutico. Debemos pensar en variantes agresivas cuando al inicio ya encontramos elementos sugestivos de extensión extratiroidea, como en este reporte.

High-cell variant papillary thyroid carcinoma, described in 1976 by Hawk and Hazard, represents 1% of differentiated carcinomas, being more aggressive and invasive than the classic form, and 80% of cases is associated with a B-RAF mutation. We present the case of a 49-year-old woman with a painful tumor on the anterolateral side of the neck, who had rapid growth, dysphonia and lateralization of the neck to the left. On thyroid ultrasound, a voluminous mixed node, predominantly solid, hypo echogenic, with micro calcifications, without separation of the fat plane with the infrahyoid muscles, was seen in the right lobe. Fine needle puncture was performed, resulting in Bethesda VI. In pre-surgical evaluation, right vocal cord paralysis was found. Total thyroidectomy was performed with central and right lateral emptying. The pathology study reported a 33 x 40 x 27 mm high cell variant papillary thyroid carcinoma in the right lobe that contacted with the Chinese ink, evaded the capsule and presented perineural invasion. Eight lymph nodes out of 18 analyzed were metastatic in compartment VI. Subsequently, a total body scan wasperformed with a minimum dose of I131 and then 150 mCi of I131 was administered. Papillary thyroid carcinoma, a high-cell variant, may initially present with loco regional involvement and its correct diagnosis has implications for prognosis and therapeutic management. We must think of aggressive variants when at the beginning we already found elements suggestive of extra thyroid extension, as in this report.

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. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non-small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.