LF

Laia Foradada

Vall d'Hebron Hospital Universitari

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Laura Soucek

Institució Catalana de Recerca i Estudis Avançats

Marie‐Eve Beaulieu

Vall d'Hebron Hospital Universitari

Jonathan R. Whitfield

Vall d'Hebron Institute of Oncology

Daniel Massó-Vallés

Vall d'Hebron Institute of Oncology

Sandra Martínez-Martín

Vall d'Hebron Institute of Oncology

Toni Jauset

Vall d'Hebron Institute of Oncology

Mariano F. Zacarías Fluck

Vall d'Hebron Institute of Oncology

Sílvia Casacuberta‐Serra

Vall d'Hebron Hospital Universitari

Miguel A. Morcillo

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

Virginia Castillo Cano

Vall d'Hebron Institute of Oncology

Cooperative Institutions

Universitat Autònoma de Barcelona

Vall d'Hebron Institute of Oncology

Vall d'Hebron Hospital Universitari

Vall d'Hebron Institut de Recerca

Instituto de Salud Carlos III

Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine

CIBBIM-Nanomedicine

Centro de Investigación Biomédica en Red

Centro de Investigación Biomédica en Red de Cáncer

Hebron University

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

Nature Medicine (2024)

Elena Garralda Marie‐Eve Beaulieu Víctor Moreno Sílvia Casacuberta‐Serra Sandra Martínez-Martín

Abstract 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. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg −1 ). ClinicalTrials.gov identifier: NCT04808362 .

Tolerability

Pharmacodynamics

Clinical endpoint

10.1038/s41591-024-02805-1

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Citations (52)

Immunohistochemical Characterisation of Classical Scrapie Neuropathology in Sheep

Journal of Comparative Pathology (2009)

Enríc Vidal Cristina Acín Laia Foradada Marta Monzón M. Márquez

Bovine spongiform encephalopathy

Astrocytosis

10.1016/j.jcpa.2009.04.002

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Citations (21)

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

Oncotarget (2018)

Toni Jauset Daniel Massó-Vallés Sandra Martínez-Martín Marie‐Eve Beaulieu Laia Foradada

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. Here, we preclinically evaluate the effect of BET inhibition making use of a new BET inhibitor, BAY 1238097, against Pancreatic Ductal Adenocarcinoma (PDAC) and Non-Small Cell Lung Cancer (NSCLC) models harboring RAS mutations both in vivo and in vitro. Our results demonstrate that BET inhibition displays significant therapeutic impact in genetic mouse models of KRAS-driven PDAC and NSCLC, reducing both tumor area and tumor grade. The same approach also causes a significant reduction in cell number of a panel of RAS-mutated human cancer cell lines (8 PDAC and 6 NSCLC). In this context, we demonstrate that while BET inhibition by BAY 1238097 decreases MYC expression in some cell lines, at least in PDAC cells its anti-tumorigenic effect is independent of MYC regulation. Together, these studies reinforce the use of BET inhibition and prompt the optimization of more efficient and less toxic BET inhibitors for the treatment of KRAS-driven malignancies, which are in urgent therapeutic need.

BET inhibitor

10.18632/oncotarget.24648

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Citations (13)

Diabetic neuropathy: Electrophysiological and morphological study of peripheral nerve degeneration and regeneration in transgenic mice that express IFNβ in β cells

Muscle & Nerve (2009)

Anna Serafín Jéssica Molín M. Márquez Ester Blasco Enríc Vidal

Abstract Diabetic neuropathy is one of the most frequent complications in diabetes but there are no treatments beyond glucose control, due in part to the lack of an appropriate animal model to assess an effective therapy. This study was undertaken to characterize the degenerative and regenerative responses of peripheral nerves after induced sciatic nerve damage in transgenic rat insulin I promoter / human interferon beta (RIP/IFNβ) mice made diabetic with a low dose of streptozotocin (STZ) as an animal model of diabetic complications. In vivo, histological and immunohistological studies of cutaneous and sciatic nerves were performed after left sciatic crush. Functional tests, cutaneous innervation, and sciatic nerve evaluation showed pronounced neurological reduction in all groups 2 weeks after crush. All animals showed a gradual recovery but this was markedly slower in diabetic animals in comparison with normoglycemic animals. The delay in regeneration in diabetic RIP/IFNβ mice resulted in an increase in active Schwann cells and regenerating neurites 8 weeks after surgery. These findings indicate that diabetic‐RIP/IFNβ animals mimic human diabetic neuropathy. Moreover, when these animals are submitted to nerve crush they have substantial deficits in nerve regrowth, similar to that observed in diabetic patients. When wildtype animals were treated with the same dose of STZ, no differences were observed with respect to nontreated animals, indicating that low doses of STZ and the transgene are not implicated in development of the degenerative and regenerative events observed in our study. All these findings indicate that RIP/IFNβ transgenic mice are a good model for diabetic neuropathy. Muscle Nerve, 2010

Diabetic Neuropathy

Neurite

Crush injury

10.1002/mus.21564

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Citations (9)

Conformational and functional variants of CD44-targeted protein nanoparticles bio-produced in bacteria

Biofabrication (2016)

Mireia Pesarrodona Yolanda Fernández Laia Foradada Alejandro Sánchez‐Chardi Oscar Conchillo‐Solé

Biofabrication is attracting interest as a means to produce nanostructured functional materials because of its operational versatility and full scalability. Materials based on proteins are especially appealing, as the structure and functionality of proteins can be adapted by genetic engineering. Furthermore, strategies and tools for protein production have been developed and refined steadily for more than 30 years. However, protein conformation and therefore activity might be sensitive to production conditions. Here, we have explored whether the downstream strategy influences the structure and biological activities, in vitro and in vivo, of a self-assembling, CD44-targeted protein-only nanoparticle produced in Escherichia coli. This has been performed through the comparative analysis of particles built from soluble protein species or protein versions obtained by in vitro protein extraction from inclusion bodies, through mild, non-denaturing procedures. These methods have been developed recently as a convenient alternative to the use of toxic chaotropic agents for protein resolubilization from protein aggregates. The results indicate that the resulting material shows substantial differences in its physicochemical properties and its biological performance at the systems level, and that its building blocks are sensitive to the particular protein source.

Biofabrication

Protein Engineering

Downstream processing

10.1088/1758-5090/8/2/025001

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Citations (18)

Abstract 3351: Myc inhibition by Omomyc impairs melanoma growth and progression through genome-wide gene expression reprogramming

Cancer Research (2018)

Mariano F. Zacarías Fluck Génesis Martín Daniel Massó-Vallés Laia Foradada Jonathan R. Whitfield

Abstract Myc encodes for a transcription factor deregulated in the vast majority of human cancers, mainly by amplification or constant upstream oncogenic signaling. Previous work from our laboratory showed that targeting Myc by transgenic expression of the Myc inhibitor Omomyc is an effective strategy to inhibit tumor progression and cause tumor regression in a wide array of mouse cancer models, without any evidence of toxicity in normal tissues. Our goal now is to assess whether Myc inhibition can be an effective approach to treat melanoma, the most dangerous form of skin cancer. For this purpose, we transfected human melanoma cell lines with a doxycycline-dependent vector expressing Omomyc-RFP and characterized the effect of Myc inhibition on proliferation and colony formation, as well as the expression of different cell cycle related proteins. We observed that Omomyc significantly reduced proliferation of a wide variety of cell lines, regardless of their driving mutations. In p53 wild type cells, Omomyc expression was accompanied by p53 stabilization and concomitant p21 upregulation, and in BRaf or NF1 mutated melanoma cells, by downregulation of cyclin D1. In order to elucidate the mechanism of action underlying this anti-tumorigenic effect, we performed a microarray analysis of A375 melanoma cells in the presence or absence of Omomyc-RFP expression. This analysis showed that Omomyc affected genome-wide gene expression. More in detail, Gene Set Enrichment Analysis showed that Omomyc significantly blunts the expression of both Myc and E2F targets, as well as RNA biogenesis, DNA replication and different cell cycle checkpoints, among many others relevant gene sets. Importantly, Omomyc significantly reduced the expression of genes related to melanoma metastases. Finally, in order to validate Omomyc therapeutic impact in vivo, A375 and SkMel147 cells were s.c. implanted into nude mice and the effect of Omomyc expression on tumor progression was evaluated. Our results show that Omomyc expression significantly impairs the growth of both cell lines, increasing the survival of tumor-bearing mice. These results combined clearly show that Omomyc-mediated Myc inhibition is an effective means to impair melanoma progression, by directly targeting Myc, inhibiting cell cycle and decreasing melanoma aggressiveness. Citation Format: Mariano F. Zacarias-Fluck, Génesis Martín, Daniel Massó-Vallés, Laia Foradada, Jonathan R. Whitfield, Marie-Eve Beaulieu, Laura Soucek. Myc inhibition by Omomyc impairs melanoma growth and progression through genome-wide gene expression reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3351.

Reprogramming

E2F

10.1158/1538-7445.am2018-3351

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

Daniel Massó-Vallés Marie‐Eve Beaulieu Toni Jauset Fabio Giuntini Mariano F. Zacarías Fluck

<div><p>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. Here we demonstrate for the first time that MYC inhibition by transgenic Omomyc is efficacious against all breast cancer molecular subtypes, including triple-negative breast cancer, where it displays potent antimetastatic properties both <i>in vitro</i> and <i>in vivo</i>. Importantly, pharmacologic treatment with the recombinantly produced Omomyc miniprotein, recently entering a clinical trial in solid tumors, recapitulates several key features of expression of the Omomyc transgene, confirming its clinical applicability to metastatic breast cancer, including advanced triple-negative breast cancer, a disease in urgent need of better therapeutic options.</p>Significance:<p>While MYC role in metastasis has been long controversial, this manuscript demonstrates that MYC inhibition by either transgenic expression or pharmacologic use of the recombinantly produced Omomyc miniprotein exerts antitumor and antimetastatic activity in breast cancer models <i>in vitro</i> and <i>in vivo</i>, suggesting its clinical applicability.</p></div>

Triple-negative breast cancer

10.1158/2767-9764.c.6550557

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Citations (0)

Supplementary Data from MYC Inhibition Halts Metastatic Breast Cancer Progression by Blocking Growth, Invasion, and Seeding

Daniel Massó-Vallés Marie‐Eve Beaulieu Toni Jauset Fabio Giuntini Mariano F. Zacarías Fluck

<p>Supplementary Figures 1-6 and Supplementary Tables 1-2</p>

Blocking (statistics)

10.1158/2767-9764.22544166

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Citations (0)

Abstract 3956: Omomyc-based cell-penetrating peptides: From proof of concept to a clinically viable anti-Myc therapy

Cancer Research (2018)

Marie‐Eve Beaulieu Toni Jauset Daniel Massó-Vallés Sandra Martínez-Martín Peter B. Rahl

Abstract Deregulation of the MYC oncoprotein drives tumorigenesis in most–if not all–cancers and generally correlates with poor prognosis, suggesting that its inhibition would be a useful therapeutic strategy. Indeed, we have shown that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer (i.e., skin, lung, pancreatic cancer and glioma), without eliciting resistance to therapy, and causes only mild, well-tolerated and reversible side effects in normal tissues. For these studies we employed a dominant negative inhibitor of Myc, called Omomyc, which is an effective inhibitor of Myc transactivation function both in vitro and in vivo. Omomyc has so far been utilized exclusively as a transgene, as a successful proof of principle whose application was believed to be solely limited to gene therapy. Here, though, we show that the purified Omomyc polypeptide itself spontaneously transduces into cancer cells and effectively interferes with MYC transcription, abrogating cell cycle and promoting apoptosis in different cancer cells, independently of their mutational profile. Efficacy of the Omomyc polypeptide in two complementary murine models of non-small cell lung cancer (NSCLC) establishes its therapeutic potential through both direct tissue delivery (intranasal) and systemic intravenous administration, providing for the first time evidence that the Omomyc polypeptide is an effective MYC inhibitor worthy of clinical development. Citation Format: Marie-Eve Beaulieu, Toni Jauset, Daniel Massó-Vallés, Sandra Martínez-Martín, Peter Rahl, Löika Maltais, Mariano F. Zacarias-Fluck, Sílvia Casacuberta-Serra, Erika Serrano del Pozo, Christopher Fiore, Laia Foradada, Virginia Castillo Cano, Matthew Guenther, Eduardo Romero Sanza, Marta Oteo, Cynthia Tremblay Tremblay, Génesis Martín, Danny Letourneau, Martin Montagne, Miguel Ángel Morcillo Alonso, Jonathan R. Whitfield, Pierre Lavigne, Laura Soucek. Omomyc-based cell-penetrating peptides: From proof of concept to a clinically viable anti-Myc therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3956.

10.1158/1538-7445.am2018-3956

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

Daniel Massó-Vallés Marie‐Eve Beaulieu Toni Jauset Fabio Giuntini Mariano F. Zacarías Fluck

<div><p>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. Here we demonstrate for the first time that MYC inhibition by transgenic Omomyc is efficacious against all breast cancer molecular subtypes, including triple-negative breast cancer, where it displays potent antimetastatic properties both <i>in vitro</i> and <i>in vivo</i>. Importantly, pharmacologic treatment with the recombinantly produced Omomyc miniprotein, recently entering a clinical trial in solid tumors, recapitulates several key features of expression of the Omomyc transgene, confirming its clinical applicability to metastatic breast cancer, including advanced triple-negative breast cancer, a disease in urgent need of better therapeutic options.</p>Significance:<p>While MYC role in metastasis has been long controversial, this manuscript demonstrates that MYC inhibition by either transgenic expression or pharmacologic use of the recombinantly produced Omomyc miniprotein exerts antitumor and antimetastatic activity in breast cancer models <i>in vitro</i> and <i>in vivo</i>, suggesting its clinical applicability.</p></div>

Triple-negative breast cancer

10.1158/2767-9764.c.6550557.v1

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Citations (0)