On January 24, 2019 The Simmons Comprehensive Cancer Center reported constantly finding drug combinations that help fight drug-resistant cancers (Press release, The Simmons Comprehensive Cancer Center, JAN 24, 2020, View Source [SID1234553752]). Researchers at the UT Southwestern Medical Center appeared to have found a new one using already approved drugs .

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The investigators were studying data from a "molecularly guided trial" in which breast cancer patients with HER2 mutations received neratinib (Puma Biotechnology’s Nerlynx), which is a HER2 inhibitor. If the disease progressed despite treatment, the researchers sequenced the DNA of the tumors. They found in the laboratory that an effective approach to battling eventual resistance to neratinib was another drug, everolimus (Novartis’ Afinitor). Everolimus is a TORC1 inhibitor often used to treat other forms of breast cancer.

"This finding may give clinicians an effective response to neratinib resistance," said Carlos L. Arteaga, director of the Simmons Cancer Center at UT Southwestern and corresponding author of the research. "That could make a real difference for patients with breast, ovarian, lung, and other cancers harboring HER2 mutations."

HER2 mutations are known to drive breast cancer and other cancers. The researchers focused on a signaling network driven by TORC1. The network is the pathway where HER2-mutant cancers develop resistance to neratinib.

"We consistently noted activation of TORC1 signaling as a mechanism of resistance to neratinib across different types of HER2-mutant cancers," said Dhivya Sudhan, a postdoctoral research fellow at the Harold C. Simmons Comprehensive Cancer Center. "Different cancer types used different strategies to escape neratinib, but they all converged on TORC1 signaling."

They evaluated the research in data from clinical trials across the country as well as in neratinib-resistant cells and tumors grown in the laboratory. Some patients, they found, already had a mutation that could possibly activate the TORC1 pathway. Others developed it. Both groups could potentially benefit from everolimus, which would extend the patient’s ability to respond to neratinib.

At this time the combination worked in cell lines, in organoids developed from patient-derived tumors, and in mice with the HER2 mutant tumors. They hope to begin testing the two-drug combo in human clinical trials.

The research was published in the journal Cancer Cell.

Earlier this week, researchers at the Broad Institute of MIT and Harvard tested about 4,518 drugs on 578 human cancer cell lines. They discovered that almost 50 had previously unrecognized anti-cancer properties. The drugs ranged from treatments for diabetes, inflammation, alcoholism and arthritis in dogs.

"We thought we’d be lucky if we found even a single compound with anti-cancer properties, but we were surprised to find so many," said Todd Golub, chief scientific officer and director of the Cancer Program at the Broad.

The research leveraged the Broad’s Drug Repurposing Hub. This Hub is made up of more than 6,000 existing drugs and molecules the U.S. Food and Drug Administration (FDA) has either already approved or have been shown to be safe in clinical trials. At the time the group conducted their study, there were 4,518 compounds in the Hub.

"Most existing cancer drugs work by blocking proteins, but we’re finding that compounds can act through other mechanisms," Steven Corsello said. Corsello is an oncologist at Dana-Farber Cancer Institute, founder of the Drug Repurposing Hub, member of the Golub lab and first author of the study, which was published in the journal Nature Cancer.

For example, some of the drugs activated a protein or stabilized a protein-protein interaction. Almost a dozen of the non-cancer drugs killed cancer cells expressing the PDE3A protein by stabilizing the PDE3A and SLFN12 protein interaction. This was an unknown mechanism.

Many of the drugs killed cancer cells by interacting with a previously unrecognized molecular target. One example is the drug tepoxalin, used to treat osteoarthritis in dogs. But the drug killed cancer cells by interacting with an unknown target in cancer cells that overexpress the MDR1 protein, which is linked to resistance to chemotherapy drugs.

The researchers were further able evaluate the cell line’s genomic features and predict which drugs could kill each cell line. Those genomic features included mutations and methylations levels, which were available in the CCLE database.

On January 24, 2020 Baylor College of Medicine reported that protein naturally produced in the body has been found to suppress breast cancer metastasis in animal models of human tumors. Researchers led by Baylor College of Medicine also found that high levels of this protein, AKAP8, predicts a better survival for breast cancer patients (Press release, Baylor College of Medicine, JAN 24, 2020, View Source [SID1234553751]).

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The findings, in the current edition of the journal Nature Communications, show that AKAP8 inhibits metastasis by interfering with the production of proteins that promote metastatic behavior in cells, and suggest strategies that may help treat metastatic cancer in the future.

"Our laboratory investigates cellular mechanisms that regulate breast cancer metastasis. In a previous study we provided the first evidence that alternative splicing, a cellular process that enables cells to switch between different forms of the same protein, can functionally control tumor metastasis," said corresponding author Dr. Chonghui Cheng, associate professor at the Lester and Sue Smith Breast Center, of molecular and human genetics and of molecular and cellular biology at Baylor.

Alternative splicing is a natural cellular process that helps cells conduct many functions, such as wound healing and embryonic development. Through alternative splicing, cells can make a large number of proteins from a limited number of genes. It would be like putting together a number of different outfits by combining in different ways a limited number of pieces of clothing. In humans, around 95 percent of all genes are processed through alternative splicing. Just recently has this process also been shown to be involved in cancer.

In that pioneering study that brought alternative splicing to the field of cancer research, Cheng and her colleagues showed that of the two distinct forms of the protein CD44 that can be produced by alternative splicing, named CD44s and CD44v, only the former contributed to cancer cell survival. These findings have been confirmed by other reports about breast cancer and also other types of cancer.

In the current study, the researchers further investigated how alternative splicing contributes to cancer metastasis by looking for proteins that regulate alternative splicing events linked to metastasis.

AKAP8 helps keep cells in a non-metastatic state
Cheng and her colleagues screened cells looking for proteins functioning as alternative splicing modulators that prevented cells from becoming metastatic. They identified a set of proteins that were potentially key for tumor metastasis regulation and focused on AKAP8.

"We studied AKAP8 in metastatic breast cancer animal model systems of cancer cells from human patients," Cheng said. "We found that depletion of the AKAP8 protein in patient cancer cells promoted breast cancer metastasis in these mouse models. Furthermore, providing an external source of AKAP8 inhibited metastasis."

Taking it all together, the results support AKAP8 as an important regulator of alternative splicing events linked to tumor metastasis. It is not only able to predict metastatic breast cancer outcomes in patients, but also can inhibit metastatic breast cancer progression in animal models.

Cheng and her colleagues continued their investigations to determine how AKAP8 mediated its metastasis-suppressing effects. They discovered that, in addition to modulating alternative splicing of CD44, AKAP8 also regulated the alternative splicing of another protein called CLSTN1. In this case, of the two forms of CLSTN1, named CLSTN1S and CLSTN1L, AKAP8 tipped the balance toward the production of the former, which was associated with preventing cells from progressing toward a metastatic state. This was a previously unknown function of CLSTN1.

"We think that modulators of alternative splicing participate in a delicate balancing act of many different cellular proteins, such as CD44 and CLSTN1. Two types of modulators play a part in keeping the balance. One type, like AKAP8, modulates alternative splicing toward the production of proteins that help cells remain in a normal state. The other type tips the balance toward proteins that promote metastatic transformation," Cheng said. "If the balance is disturbed, tumor progression can be promoted. By investigating how the balance is kept and the factors that disturb the balance, we hope to understand a new layer of regulation of tumor metastasis and gain insights that could lead to treatments for metastatic cancer, a deadly disease."

Other contributors to this work include Xiaohui Hu, Samuel E. Harvey, Rong Zheng, Jingyi Lyu, Caitlin L. Grzeskowiak and Kenneth L. Scott at Baylor; and Emily Powell and Helen Piwnica-Worms at The University of Texas MD Anderson Cancer Center, Houston.

This research was supported in part by grants from the US National Institutes of Health (5F30CA196118, R01 CA182467, R01GM110146 and R35GM131876) and CPRIT Scholar in Cancer Research grant RR160009.

On January 24, 2020 Bionetix, a biotech company developing novel oncology drugs; ProQinase, an oncology-focused contract research organization (CRO) recently acquired by Reaction Biology Corporation (Malvern/PA, USA); and MercachemSyncom, a chemistry CRO specializing in medicinal chemistry and comprehensive medicinal chemistry (CMC), reported they have signed a joint multiyear integrated drug-discovery project, starting from target identification (TI) up to clinical candidate selection on an undisclosed target aimed at acute myeloid leukemia (AML) (Press release, Mercachem, JAN 24, 2020, View Source [SID1234553571]). The goal of the three-party team is to advance the project to the clinical phase by 2023. The total investment sum is "significant, of multimillion Euros", but details are not being disclosed.

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"We are excited to start this new project with MercachemSyncom and ProQinase," said Dr. DooYoung Jung, CEO of Bionetix. "They have proven their quality in another project of ours, which is currently in the early development phase. When this new opportunity came up, our decision was quick and easy. We are convinced that the team will advance this program very efficiently."

Dr. Frank Leemhuis, Managing Director of MercachemSyncom, commented: "Our skilled and experienced team has a proven track record in medicinal chemistry and CMC and built valuable research assets, as the result of a consistent innovation strategy. This research project is an opportunity to build on these qualities, with the goal of serving and creating value for our client. ProQinase is ourtrusted biology partner, through years of collaboration. Together with Bionetix, we look forward to making essential contributions to this oncology program."

"We are very grateful for our long-lasting partnership with MercachemSyncom, which enables us to deliver combined top-class scientific expertise to Bionetix," said Dr. Sebastian Dempe, Chief Executive Officer of ProQinase. "This new opportunity of a multiyear collaboration, utilizing our entire breadth of oncology preclinical services, aims to develop a high-value asset for our mutual client. Working together on solid but flexible research plans, combined with efficiency, allow for short lead times and robust datageneration processes, which are key to the success of such integrated drug-discovery projects. With MercachemSyncom, we will make sure that our promises to Bionetix are met."

On January 24, 2020 Kitov Pharma Ltd. ("Kitov") (NASDAQ/TASE: KTOV), a clinical-stage company advancing first-in-class therapies to overcome tumor immune evasion and drug resistance, reported receipt from the European Patent Office (EPO) of a Notice of Intention to Grant for its patent application entitled "Combinations of IRS/STAT3 Dual Modulators and Anti-Cancer Agents for Treating Cancer (Press release, Kitov Pharmaceuticals , JAN 24, 2020, View Source [SID1234553552])." The patent, which expires in 2036, covers the treatment of NT-219, the company’s novel dual inhibitor of IRS 1/2 and STAT3, in combination with EGFR antibodies and inhibitors.

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Kitov is currently advancing NT-219 in combination with cetuximab, an EGFR antibody, as a second-line or third-line therapy for the treatment of recurrent and metastatic squamous cell carcinoma of the Head & Neck Cancer (SCCHN). Kitov plans to initiate a phase 1/2 study in the second quarter of 2020.

"We believe strongly in our rationale for combining NT-219 with cetuximab and we are very pleased with this new addition to our patent estates in Europe," said Isaac Israel, Kitov’s chief executive officer. "Cetuximab is currently the only targeted FDA-approved treatment option for patients with a progressed disease following both prior platinum-based therapy and pembrolizumab. NT-219 has the potential to prevent tumor resistance and re-sensitize tumors to the anti-cancer activity of EGFR inhibitors, making this combination a very attractive drug candidate that will hopefully address the unmet medical need for recurrent and metastatic Head and Neck cancer patients."

On January 24, 2020 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the Phase III IMvigor010 study evaluating Tecentriq (atezolizumab) as an adjuvant (after surgery) monotherapy treatment did not meet its primary endpoint of disease-free survival (DFS) compared to observation in people with muscle-invasive urothelial cancer (MIUC) (Press release, Hoffmann-La Roche, JAN 24, 2020, View Source [SID1234553544]). Safety for Tecentriq appeared consistent with the known safety profile of the medicine, and no new safety signals were identified.

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"Reducing the risk that muscle-invasive urothelial cancer will recur after surgery is very difficult, and we are disappointed that we were not able to significantly prolong disease-free survival," said Levi Garraway, M.D., Ph.D., Chief Medical Officer and Head of Global Product Development. "We remain committed to exploring the potential benefits of immunotherapy for more people with early cancers."

The goal in treating MIUC early is to reduce the risk of the disease recurring or spreading to other parts of the body. More treatment options following surgery are needed as approximately half of people with MIUC will develop a recurrence of their disease within 2 years of surgery.1

In addition to ongoing Phase III studies in early and advanced bladder cancer, Roche has an extensive development programme for Tecentriq, including multiple ongoing and planned Phase III studies across several types of lung, genitourinary, skin, breast, gastrointestinal, gynaecological, and head and neck cancers. This includes studies evaluating Tecentriq both alone and in combination with other medicines.

About the IMvigor010 study
IMvigor010 is a global Phase III, open-label, randomised, controlled study designed to evaluate the efficacy and safety of adjuvant treatment with Tecentriq compared to observation in 809 people with MIUC, who are at high risk for recurrence following resection. The primary endpoint is DFS as assessed by investigator, which is defined as the time from randomisation to invasive urothelial cancer recurrence or death.

About bladder cancer and muscle-invasive urothelial cancer
In 2018, there were over half a million new cases of bladder cancer diagnosed globally, with approximately 200,000 deaths from the disease.2 Urothelial cancer is the most common type of bladder cancer, accounting for about 90–95% of all cases.3 MIUC is a type of urothelial cancer that has spread into the muscle of the bladder, ureter or renal pelvis.4 Approximately 25% of new cases of bladder cancer are diagnosed with muscle-invasive disease,5 which is associated with a poorer prognosis than non-MIUC.4

About Tecentriq
Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1, which is expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the activation of T cells. Tecentriq is a cancer immunotherapy that has the potential to be used as a foundational combination partner with other immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers. The development of Tecentriq and its clinical programme is based on our greater understanding of how the immune system interacts with tumours and how harnessing a person’s immune system combats cancer more effectively.

Tecentriq is approved in the US, EU and countries around the world, either alone or in combination with targeted therapies and/or chemotherapies in various forms of non-small cell and small cell lung cancer, certain types of metastatic urothelial cancer, and in PD-L1-positive metastatic triple-negative breast cancer.

About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with Tecentriq to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients.