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New research has identified a protein that makes melanoma, the most serious type of skin cancer, more aggressive by giving cancer cells the ability to change the shape of their nucleus -- a characteristic which allows the cells to migrate and spread around the body. Research led by Queen Mary University of London, King's College London and the Francis Crick Institute has identified a protein that makes melanoma, the most serious type of skin cancer, more aggressive by giving cancer cells the ability to change the shape of their nucleus -- a characteristic which allows the cells to migrate and spread around the body. The study, published today in Nature Cell Biology, modelled the behaviour of aggressive melanoma cells that are able to change the shape of their nucleus to overcome the physical constraints that cancer cells encounter when they migrate through tissues. The study found that these aggressive melanoma cells harboured high levels of a protein called LAP1 and that increased levels of this protein were linked to poor prognosis in melanoma patients. Melanoma is a type of skin cancer that can spread to other organs in the body. Cancer spread or 'metastasis' is the leading cause of cancer-related deaths. While metastasis has been extensively studied, the mechanisms by which it occurs are poorly understood. The findings from the study shed new light on a mechanism of melanoma progression and could pave the way for the development of new ways to target melanoma spread. The study The study was co-led by Professor Victoria Sanz-Moreno from Queen Mary's Barts Cancer Institute and Dr Jeremy Carlton from King's College London and The Francis Crick Institute, and primarily funded by Cancer Research UK, the Wellcome Trust and Barts Charity. In the study, the team challenged aggressive and less-aggressive melanoma cells in laboratory experiments to migrate through pores in an artificial membrane that were smaller than the size of their nucleus. The aggressive cells were from a site of metastasis in a patient with melanoma, and the less-aggressive cells were from the original or 'primary' melanoma tumour of the same patient. To metastasise, cancer cells need to break away from the primary tumour, travel to another part of the body and start growing there. However, the dense surroundings of a tumour make this physically difficult for cancer cells. Cells contain a large, stiff structure called the nucleus that stores the cell's genetic information, but which also restricts the ability of a cell to move through the tight gaps in the tumour's environment. For cancer cells to squeeze through these gaps, they need to make their nucleus more malleable. Imaging conducted after the migration experiments showed that the aggressive cells were able to move through the pores more effectively than the less-aggressive ones by forming bulges at the edge of their nucleus called 'blebs'. Genetic analyses of the melanoma cells revealed that the aggressive cells that formed the blebs contained higher levels of the LAP1 protein, which sits within the membrane that surrounds the nucleus (called the nuclear envelope). Dr Jeremy Carlton, whose laboratory is interested in understanding the dynamics of membrane-bound structures within cells, said: "The nuclear envelope is tethered to the underlying nucleus, and our investigations show that the LAP1 protein loosens this tethering, allowing the nuclear envelope to bulge away and form blebs that make the nucleus more fluid. As a result, the cancer cells could squeeze through gaps that would normally stop them." When the team blocked the production of the LAP1 protein in aggressive cells and re-challenged them to migrate through pores in laboratory experiments, they found that the cells were less able to form nuclear envelope blebs and less able to squeeze through these gaps. The team also observed the same pattern of LAP1 expression in melanoma samples from patients. LAP1 levels were higher in tissue samples taken from sites of metastasis in melanoma patients compared to the levels found in primary tumours. The patients that had high levels of LAP1 in the cells around the edge of the primary tumour had more aggressive cancer and poorer outcomes, suggesting that the protein could be used to identify subpopulations of melanoma patients that may be at higher risk of aggressive disease. Professor Sanz-Moreno, whose research group is interested in understanding how cancer cells communicate with their environment to promote their growth and spread, said: "Melanoma is the most aggressive and deadly type of skin cancer. By combining the expertise of my laboratory with that of Dr Carlton's, we have gained new mechanistic understanding of how LAP1 contributes to melanoma progression, and have shown that LAP1 is a key regulator of melanoma aggressiveness in laboratory and patient models." "Because LAP1 is expressed in such high levels in metastatic cells, interfering with this molecular machinery could have a big impact on cancer spread. There are currently no drugs that target LAP1 directly, so looking to the future we would like to investigate ways to target LAP1 and nuclear envelope blebbing to see if it is possible to block this mechanism of melanoma progression." The team would like to investigate whether nuclear envelope blebbing driven by LAP1 occurs in other cells that make up and move through a tumour's environment, such as immune cells, to determine if this process in other cells helps or hinders the progression of cancer. Dr Iain Foulkes, Executive Director of Research and Innovation at Cancer Research UK, which partly funded the study, said: "Studies like this one are a perfect example of why Cancer Research UK is passionate about funding research that furthers our knowledge of what cancer does to the biology of our bodies, in addition to research that focuses on what's happening in the clinic. This new understanding of how the nucleus of a melanoma cell can become more fluid to move around the body is useful for building our knowledge of how cancer works and opens up a new avenue of investigation into ways to make it harder for cancer to spread." The first author of the study, Dr Yaiza Jung, conducted the work as part of her PhD funded by The Francis Crick Institute and King's College London.

CAMBRIDGE, Mass., Oct. 18, 2021 (GLOBE NEWSWIRE) -- Alphageneron Pharmaceuticals, Inc. (“Alphageneron” or the “Company”), a clinical stage pharmaceutical company with a robust product portfolio of autologous and allogeneic natural killer (“NK”) cell, allogeneic CAR NK cell and antibody-based therapies targeting highly resistant tumors and viral infections, announces the successful completion of a pre-IND (“Investigational New Drug”) meeting with the U.S. Food and Drug Administration (“FDA”) regarding a proposed multi-site Phase II Clinical Trial plan for its ENKASTIM™ autologous NK cell therapy for treating advanced (stage III and stage IV) non-small cell lung cancer (“NSCLC”). “We are delighted with the outcome of the Pre-IND meeting with the US FDA which was supported by clinical data from a prior Phase II Clinical Trial involving patients with advanced (stage IIIb) NSCLC in Germany. Although the number of patients was small, the prior Phase II Clinical Trial demonstrated the therapy was safe and had promising signs of efficacy in the most commonly diagnosed cancer and the leading cause of cancer deaths worldwide.” The pre-IND meeting was supported by two previously completed clinical trials in Germany, both approved by the Paul Ehrlich Institute (German ‘FDA’). A Phase I clinical trial conducted with eleven (11) metastatic colorectal cancer patients and one (1) NSCLC patient who received ENKASTIM™ after Standard of Care (SOC), demonstrated safety and signs of efficacy. A Phase IIa clinical trial (randomized, controlled) involving fourteen (14) patients with advanced (Stage IIIb) NSCLC reported that of the seven (7) patients treated with ENKASTIM™ after SOC radio-chemotherapy, five (5) patients experienced a clinical benefit (71%), including one complete response (CR) and one partial response (PR). In the control group of seven (7) patients who received SOC RCT alone, only two (2) patients experienced a clinical benefit. One of the patients who received ENKASTIM™ after SOC and went on to receive OPDIVO® (nivolumab), a PD-1 checkpoint inhibitor, achieved 33 months of Progression-free survival (PFS). This contrasts with a median survival of 9 months for historic controls.1, 2 “We are delighted with the outcome of the Pre-IND meeting with the US FDA which was supported by clinical data from a prior Phase II Clinical Trial involving patients with advanced (stage IIIb) NSCLC in Germany. Although the number of patients was small, the prior Phase II Clinical Trial demonstrated the therapy was safe and had promising signs of efficacy in the most commonly diagnosed cancer and the leading cause of cancer deaths worldwide.” said A. Graham Pockley, PhD, Chief Scientific Officer of Alphageneron. ”Based upon our recent FDA interaction, we are working diligently to finalize the protocol design to initiate our first multi-site Phase II Clinical Trial to treat patients with advanced (stage III and IV) NSCLC in 2022, an important milestone for the company.” added Robert K. Brooks, JD, Chairman and Chief Executive Officer of Alphageneron. Alphageneron is preparing to IND for a large (up to n=250) multi-site open label First In Class Phase IIa Clinical Trial administering ENKASTIM™ autologous NK Cell Therapy, after SOC, in two cohorts of Advanced NSCLC patients, namely Cohort A, patients with (stage IV) metastatic NSCLC; and, Cohort B, patients with advanced (stage III) NSCLC. The FDA’s Pre-IND teleconference meeting and written response suggestions help define the IND protocol for a proposed Phase II clinical study that could lead to future clinical registration trials or towards commercial approval. “I am excited about the potential for this proposed Phase II clinical trial of ENKASTIM™ NK cell therapy to address a significant unmet clinical need for patients with metastatic or advanced NSCLC,” stated Yanis Boumber, MD, PhD, Associate Professor, a Thoracic, Head & Neck Medical Oncologist at Feinberg School of Medicine, Northwestern University, Chicago, IL, and a Scientific Advisor to Alphageneron. About Advanced NSCLC Lung cancer is the leading cause of cancer-related mortality in the world. In 2020, over 2 million people were diagnosed with lung cancer, and 1.8 million died of the disease (WHO). An estimated 85% of lung cancer is NSCLC. When NSCLC is diagnosed as stage III or stage IV, it is considered advanced; and, 40% of NSCLC patients present at an advanced stage. There remains a high unmet clinical need to improve the treatment of advanced NSCLC that has a poor prognosis. The global market for NSCLC therapeutics was $16B in 2018 and is expected to reach $42B by 2025 (Fortune Business Insights). About ENKASTIM™ NK Cell Therapy ENKASTIM™ is an autologous unmodified NK cell therapy that activates the patient’s own NK cells to target cancers expressing membrane Hsp70 (“mHsp70”), a cancer-specific biomarker which is highly expressed on malignant cancer cells, but not on normal cells. ENKASTIM™ is manufactured by ex vivo incubation of a patient’s peripheral blood mononuclear cells (“PBMCs”), obtained by leukapheresis in an out-patient setting, with a patented Hsp70-derived synthetic peptide (named “TKD”) and low-dose interleukin-2 (“IL-2”) for under five (5) days, after which the cells are reinfused into the patient. About Alphageneron Pharmaceuticals Alphageneron is a privately held clinical-stage biopharmaceutical company developing autologous and allogeneic natural killer (NK) cell, allogeneic Chimeric Antibody Receptor (CAR) NK cell, and antibody-based cancer therapeutics, all supported by a Companion Diagnostic. In 2020, Alphageneron signed an Exclusive Option to Purchase Agreement with Multimmune, GmbH, Munich, Germany; as well as, an Exclusive License Agreement, of its therapeutic and diagnostic technology, for all indications worldwide. Forward-looking Statement Statements in this message that are not based on historical or current facts, and constitute "forward-looking statements" within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the actual results, events or developments to be materially different from any future results, events or developments expressed or implied by such forward-looking statements. Although Alphageneron believes that expectations conveyed by the forward-looking statements are reasonable based on the information available to it on the date such statements were made, no assurances can be given as to the future results, approvals or achievements. Given these uncertainties, readers are cautioned not to place undue reliance on such forward-looking statements, and should assume the Company has no obligation to update forward-looking statements except as otherwise required by applicable law. 1Krause SW, Gastpar R, Andreesen R, Gross C, Ullrich H, Thonigs G, et al. Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: A clinical phase I trial. Clin Cancer Res (2004) 10:3699-3707. 2Multhoff G, Seier S, Stangl S, Sievert W, Shevtsov M, Werner C, et al. Targeted natural killer cell based adoptive immunotherapy for the treatment of patients with NSCLC after radiochemotherapy – a randomized phase II clinical study. Clinical Cancer Research (2020) 26:5368-5379. doi:10.1158/1078-0432.CCR-20-1141 Contacts Alphageneron Pharmaceuticals Headquarters Tel. (617) 520-6659 Florida office Tel. (754) 755-8414 info@Alphageneron.com