On February 21, 2022 Published in Cancer Research Communications (1), a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), findings reported by investigators of the Vall d’Hebron Institute of Oncology’s (VHIO) Models of Cancer Therapies Group (Vall d’Hebron Barcelona Hospital Campus), and VHIO-born spin-off Peptomyc S.L., show that MYC inhibition is anti-metastatic in breast cancer (Press release, Peptomyc, FEB 21, 2022, View Source [SID1234608354]).

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The deregulation of the pleiotropic and ubiquitous MYC oncoprotein is implicated in almost all human cancers, and while its role as a promoter of tumorigenesis is beyond doubt, its function in the process of metastasis remains controversial. Contrasting reports suggest both a pro-metastatic and anti-metastatic function of MYC have largely precluded research assessing MYC inhibitors in the metastatic setting.

Thanks to two decades of research pioneered by Laura Soucek and her team, as well as the dedicated work of other groups, MYC inhibition is gaining pace in entering the clinic. Historically considered as an undruggable target, MYC now officially occupies a top spot on the most-wanted list of targets in cancer therapy.

Having shown potent anti-tumor activity of the MYC inhibitor Omomyc in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, Laura’s group and her Peptomyc team are developing viable, non-toxic pharmacological options for MYC targeting in the clinic.

"Considering the results of our previous studies that have clearly demonstrated Omomyc’s efficacy in primary tumors, we hypothesized that targeting MYC could also be efficacious against metastatic breast cancer," said Laura Soucek, corresponding author of this present study, Co-Founder & Chief Executive Officer (CEO) of Peptomyc, and an ICREA Research Professor.

Ringing in MYC inhibition in the metastatic setting
Metastases are genetically unstable. Information from a patient’s primary tumor might not mirror the metastasis, and one metastasis may vary from another, thus hampering the benefits of targeted therapies. Based on their data indicating the efficacy of MYC inhibition independently of the mutational profile of the tumor, the investigators hypothesized that this approach could overcome th challenge.

They also sought to establish if MYC inhibition could revert MYC’s promotion of epithelial-mesenchymal transition (EMT) and dedifferentiation, two important hallmarks of cancer metastasis.

The promise of Omomyc as a potential anti-metastatic therapy in breast cancer
To evaluate Omomyc’s efficacy against breast cancer and metastasis, the researchers used a panel of breast cancer cell lines, representative of all molecular subtypes of the disease. Assessing the transgenically expressed Omomyc first, they observed therapeutic impact in these cell lines and in cell-derived in vivo xenograft models.

They then confirmed that the same therapeutic impact can be achieved pharmacologically using the purified Omomyc mini-protein which demonstrated efficacy in cell lines in vitro, as well as in vivo, in cell-derived and patient-derived xenograft (PDX) models.

Results of this present study (1) shed important light on the efficacy of MYC inhibition in the metastatic setting, with particular focus on triple-negative breast cancer (TNBC). The investigators demonstrate for the first time that MYC inhibition by Omomyc is effective against TNBC by displaying potent anti-metastatic activity in vivo.

"Our results illuminate the relevance of MYC inhibition in metastatic disease, and are particularly timely now that MYC inhibitors, including our first Omomyc-derived compound, OMO-103, are reaching the clinic," added Laura Soucek.

Notably, OMO-103 entered clinical trials in May 2021, and is being tested in patients with various solid tumors in the Phase I/IIa MYCure study (2).

"We have now demonstrated that MYC inhibition by Omomyc exerts a dramatic effect on the metastatic process, from tumor growth, invasion to seeding. Findings evidenced a striking reduction in both primary tumor and metastatic growth. In some cases, metastases were even eradicated," said Daniel Massó-Vallés, first author of this study and a Postdoctoral Researcher and Project Manager at Peptomyc.

This study shows the promise of Omomyc as an anti-metastatic therapy against breast cancer and also challenges the controversial notion that MYC inhibition potentiates, rather than inhibits, tumor cell invasion and metastasis.

Results support the inclusion of metastatic TNBC patients in the ongoing MYCure trial, uphold MYC’s essential role in all aspects of tumorigenesis, and could ultimately lead to improved survival in this patient population.

This research was carried out in collaboration with investigators from other VHIO groups including Violeta Serra (PI, Experimental Therapeutics Group), and Joaquín Arribas (PI, Growth Factors Group), and researchers at CIEMAT (Madrid, Spain), and the Karolinska Institutet (Stockholm, Sweden).

This project was mainly funded by grants received from the Agència de Gestió d’Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants), Spanish Ministry of Science and Innovation, Spanish Ministry of Science and Technology – Institute of Health Carlos III, European Research Council (ERC), and the FERO Foundation.

References:

Daniel Massó-Vallés, Marie-Eve Beaulieu, Toni Jauset, Fabio Giuntini, Mariano F. Zacarías-Fluck, Laia Foradada, Sandra Martínez-Martín, Erika Serrano, Génesis Martín- Fernández, Sílvia Casacuberta-Serra, Virginia Castillo Cano, Jastrinjan Kaur, Sergio López- Estévez, Miguel Ángel Morcillo, Mohammad Alzrigat, Loay Mahmoud, Antonio Luque-García, Marta Escorihuela, Marta Guzman, Joaquín Arribas, Violeta Serra, Lars-Gunnar Larsson, Jonathan R. Whitfield & Laura Soucek. MYC inhibition halts metastatic breast cancer progression by blocking growth, invasion and seeding. Cancer Res Commun. 2022;2:110–30. doi: 10.1158/2767-9764.CRC-21-0103.
Phase 1/2 Study to Evaluate Safety, PK and Efficacy of the MYC-Inhibitor OMO-103 in Solid Tumours (MYCure). ClinicalTrials.gov Identifier: NCT04808362.

On February 21, 2022 Mission Therapeutics ("Mission"), a drug discovery and development company focused on protein homeostasis by selectively inhibiting deubiquitylating enzymes (DUBs), reported that its CEO, Anker Lundemose, will attend and present at the next event in the BMO Biopharma Spotlight Series: Protein – Degraders and Other Next Gen Technologies, on Thursday, 24 February 2022 (Press release, Mission Therapeutics, FEB 21, 2022, View Source [SID1234608353]).

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The virtual event will focus on the therapeutic area of protein degraders and other emerging technologies, with an agenda consisting of fireside chats, expert presentations, and topical panels.

Dr Lundemose will be available for one-to-one meetings as well as presenting as part of the Private Company Spotlights panel and Q&A at 11.20 ET.

This will be the sixth event in the BMO Biopharma Spotlight series of webinars, which explore different therapeutic areas and enable KOLs, public companies, and key players in the private sector to discuss their scientific research and technological approaches.

On February 21, 2022 MannKind Corporation (Nasdaq: MNKD) reported that it will release its 2021 fourth quarter and full year financial results, and its management will host a conference call to discuss the financial results and corporate updates at 5:00 p.m. (Eastern Time) on Thursday, February 24, 2022 (Press release, Mannkind, FEB 21, 2022, View Source [SID1234608352]).

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Presenting from the Company will be its Chief Executive Officer Michael Castagna and Chief Financial Officer Steven Binder.

Those interested in listening to the conference call live via the internet may do so by visiting the Investors page of the Company’s website at mannkindcorp.com under Events & Presentations.

On February 21, 2022 BioNTech SE (Nasdaq: BNTX, "BioNTech") and Medigene AG (FSE: MDG1, Prime Standard, "Medigene"), a clinical-stage immuno-oncology company focusing on the development of T cell immunotherapies, reported that they have entered a multi-target research collaboration to develop T cell receptor (TCR) based immunotherapies against cancer (Press release, BioNTech, FEB 21, 2022, View Source [SID1234608351]). The initial term of the collaboration is three years.

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Medigene will contribute its proprietary TCR discovery platform for the development of TCRs against multiple solid tumor targets nominated by BioNTech. Medigene’s automated, high throughput TCR discovery platform is designed to bypass central tolerance to yield high affinity TCRs. T cell therapy has become a disruptive medical innovation in the treatment of patients with cancer. Engineered TCR-modified T cells (TCR-T cells) are reprogrammed to express a TCR that can recognize specific antigens only present on tumor cells, thereby enabling a precise and potent immune response to attack a patient’s tumor.

"This collaboration with Medigene expands our cell therapy portfolio and TCR discovery capabilities, and further strengthens our ability to be a leader in the rapidly emerging field of engineered cell therapies," said Ugur Sahin, M.D., Chief Executive Officer and Co-Founder of BioNTech. "We look forward to working closely with Medigene to develop new treatments which address solid tumors with high unmet medical need."

Prof. Dolores Schendel, Chief Executive Officer and Chief Scientific Officer at Medigene: "Medigene is at the forefront of the development of TCR-T therapies for oncology. The sale and licensing deal with BioNTech is an important validation from a global leading biotech company of our proprietary technologies to discover and characterize highly specific TCRs and empower resulting TCR-T cells to fight solid tumors. This partnership provides Medigene with meaningful financial resources to fuel our next generation development programs targeting potentially novel tumor-specific "dark matter" antigens, further tools to enhance T-cell-based immunotherapies, as well as additional potential strategic deals with future milestone payments and royalties."

BioNTech will acquire Medigene’s next generation preclinical TCR program, which combines TCR-4 of Medigene’s MDG10XX program targeting PRAME with Medigene’s proprietary PD1-41BB switch receptor technology. BioNTech will also obtain the exclusive option to acquire additional existing TCRs in Medigene’s discovery pipeline and will receive licenses to the company’s PD1-41BB switch receptor and precision pairing library. This has the potential to augment TCR cell therapy efficacy and can be applied to all BioNTech cell therapy programs.

Under the terms of the agreement, Medigene will receive EUR 26 million upfront, as well as research funding for the period of the collaboration. BioNTech will be responsible for global development and hold exclusive worldwide commercialization rights on all TCR therapies resulting from this research collaboration. Medigene will be eligible to receive development, regulatory and commercial milestone payments up to a triple digit million EUR amount per program in addition to tiered deferred option payments on global net sales for products based on TCRs arising from the collaboration and royalties on products utilizing at least one of the licensed technologies.

On February 21, 2022 AstraZeneca reported that Positive high-level results from the pivotal DESTINY-Breast04 Phase III trial showed Enhertu (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) in patients with HER2-low unresectable and/or metastatic breast cancer regardless of hormone receptor (HR) status versus physician’s choice of chemotherapy (Press release, AstraZeneca, FEB 21, 2022, View Source [SID1234608350]).

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Enhertu is a HER2-directed antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

All patients in the trial received a HER2 test, and the results were centrally confirmed. HER2-low status was defined as an immunohistochemistry (IHC) score of 1+ or IHC 2+ with a negative in-situ hybridisation (ISH) score.

Up to 55% of all patients with breast cancer have tumours with a HER2 IHC score of 1+, or 2+ in combination with a negative ISH test, a level of HER2 expression not currently eligible for HER2-targeted therapy.1,2 HER2-low expression occurs in both HR-positive and HR-negative disease.3

HER2 testing is well established to determine an appropriate treatment strategy in metastatic breast cancer. Targeting the lower range of HER2 expression may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.4 Currently, chemotherapy remains the only treatment option both for patients with HR-positive tumours following progression on endocrine (hormone) therapy, and for those who are HR-negative.5

DESTINY-Breast04 met its primary endpoint, where Enhertu demonstrated superior PFS in previously treated patients with HR-positive HER2-low metastatic breast cancer compared to the standard-of-care chemotherapy. The trial met the key secondary endpoint of PFS in patients with HER2-low metastatic breast cancer regardless of HR status (HR-positive or HR-negative). The trial also met the key secondary endpoints of OS in patients with HR-positive disease and in patients regardless of HR status at interim analysis.

The safety profile of Enhertu was consistent with previous clinical trials, with no new safety concerns identified. Overall interstitial lung disease (ILD) rates were consistent with that observed in late-line HER2-positive breast cancer trials of Enhertu, with a lower rate of Grade 5 ILD observed as determined by an independent adjudication committee.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: "Today’s historic news from DESTINY-Breast04 could reshape how breast cancer is classified and treated. A HER2-directed therapy has never-before shown a benefit in patients with HER2-low metastatic breast cancer. These results for Enhertu are a huge step forward and could potentially expand our ability to target the full spectrum of HER2 expression, validating the need to change the way we categorise and treat breast cancer."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: "Enhertu continues to redefine the treatment of HER2-targetable cancers. DESTINY-Breast04 is the first ever Phase III trial of a HER2-directed therapy in patients with HER2-low metastatic breast cancer to show statistically significant and clinically meaningful benefit in progression-free and overall survival compared to standard treatment. We look forward to sharing the detailed findings of DESTINY-Breast04 with the medical community and initiating discussions with regulatory agencies globally with the goal of bringing Enhertu to patients with metastatic breast cancer previously considered to be HER2-negative."

The data will be presented at a forthcoming medical meeting and shared with global health authorities.

Enhertu (5.4mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

Enhertu is being further assessed in a comprehensive clinical development programme evaluating efficacy and safety across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers.

Notes

Breast cancer and HER2 expression
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.6 More than two million cases of breast cancer were diagnosed in 2020 resulting in nearly 685,000 deaths globally.6

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers, and is one of many biomarkers expressed in breast cancer tumours.7 HER2 expression is currently defined as either positive or negative, and is determined by an IHC test which measures the amount of HER2 protein in a cancer cell, and/or an ISH test which counts the copies of the HER2 gene in cancer cells.7,8 HER2-positive cancers are defined as IHC 3+ or IHC 2+/ISH+, and HER2-negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.7

DESTINY-Breast04
DESTINY-Breast04 is a global, randomised, open-label, registrational Phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive (n=480) or HR-negative (n=60) HER2-low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomised 2:1 to receive either Enhertu or chemotherapy.

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR-positive disease based on blinded independent central review (BICR). Key secondary endpoints include PFS based on BICR in all randomised patients (regardless of HR status), OS in patients with HR-positive disease and OS in all randomised patients (regardless of HR status). Other secondary endpoints include PFS based on BICR and investigator assessment, duration of response based on BICR and safety.

DESTINY-Breast04 enrolled approximately 540 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

Enhertu (5.4mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

Enhertu (6.4mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

Enhertu development programme
A comprehensive development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for Enhertu are currently under review in Europe, Japan, the US and several other countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen based on the results from the DESTINY-Breast03 trial.

Enhertu also is currently under review in Europe for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2 based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (referred to as Daiichi Sankyo) and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death.

AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumour environment.

AstraZeneca aims to continue to transform outcomes for HR-positive breast cancer with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and the next-generation oral selective oestrogen receptor degrader (SERD) and potential new medicine camizestrant.

PARP inhibitor Lynparza (olaparib) is a targeted treatment option for metastatic breast cancer patients with an inherited BRCA mutation. Lynparza has also demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival versus placebo in the adjuvant treatment of patients with germline BRCA-mutated HER2-negative early breast cancer. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research Lynparza in metastatic breast cancer patients with an inherited BRCA mutation and are exploring new opportunities to treat these patients earlier in their disease.

Building on the first approval of Enhertu, in previously treated HER2-positive metastatic breast cancer, AstraZeneca and Daiichi Sankyo are exploring its potential in earlier lines of treatment and in new breast cancer settings.

To bring much needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is testing immunotherapy Imfinzi (durvalumab) in combination with other oncology medicines, including Lynparza and Enhertu, evaluating the potential of AKT kinase inhibitor, capivasertib, in combination with chemotherapy, and collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.