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ALK Activation as a target of TRAanslational Science (ALKATRAS): Break free from cancer

Periodic Reporting for period 2 - ALKATRAS (ALK Activation as a target of TRAanslational Science (ALKATRAS): Break free from cancer)

Reporting period: 2017-09-01 to 2019-08-31

The objectives of ERIA (The European Research Initiative for ALK-Related Malignancies) as a network of scientists across Europe, is to coordinate and conduct multidisciplinary research efforts into Anaplastic Lymphoma Kinase (ALK)-driven cancers predominantly Anaplastic Large Cell Lymphoma (ALCL) and neuroblastoma – both being largely paediatric malignancies. Embedded into this established international research network, the ALK as a target of translational science (ALKATRAS) programme was developed to:

1- nurture and provide an excellent training environment to a cohort of 15 Early Stage Researchers (ESRs) to become confident, competent, independent and well-connected European scientists

2- facilitate research into ALK-related malignancies with the aim of informing more efficient, less toxic therapies

3- encourage networking across Europe of all parties with an interest in paediatric ALK-related cancers and to widen the net of our public outreach.

4- provide a focused platform for data presentation and discussion of latest advances, research findings related to ALK-induced cancers, specifically neuroblastoma and lymphoma

In achieving these aims, we have conducted research that has highlighted the mechanisms of tumour development as they relate to aberrant expression of the ALK protein resulting in multiple research papers published in open access journals as well as review articles which are of great benefit to the academic and clinical research communities to assist in teaching, training and improving general understanding of tumorigenic processes. We have also successfully trained 15 early stage researchers who will be able to move on in their careers to disseminate their research findings and contribute to society by continuing to work in this or a related field. The early stage researchers were recruited from all over the world and conducted research in a lab in a different country to their own facilitating cross-cultural interactions. All of the researchers also spent time in industry as well as another academic lab developing networks of peers and colleagues. The network will continue to work together into the future to address the clinical problem that is improving the survival and treatment outcome of patients with ALK-expressing malignancies.
In the first year, the large majority of time was spent on project management; we recruited 15 ESR from across the world. These students came from a variety of countries ranging from Mexico to India and were two thirds female. In order to facilitate management of ALKATRAS, we also recruited a project manager who was responsible for organisation and administration tasks, who has been indispensable putting in place a management structure. A training programme was developed consisting of compulsory and optional network-wide elements as well as local training events and secondments. All secondments were conducted, with ESRs attending one secondment in an industrial setting and the other in an academic lab. We also completed all of the compulsory training events with a workshops on epigenetics, genome analysis, communication, autophagy, business and science, ethics in science and a complementary skills workshop. All of the courses received excellent feedback from the students. All of our ESR have also attended multiple local training activities ranging from lab health and safety to specific training in techniques. Dissemination and outreach activities have also been a great success with many of our students having communicated their research activities through poster presentations at multiple conferences as well as via social media, in particular podcasts published on the ALKATRAS and Naked Scientist websites as well as blogs. We also produced a whole issue of the journal 'Cancers' by writing a series of review articles in collaboration with one another to disseminate our research activities to a wider audience. Research articles have also been published by the network with many ESR involved in their production and fostered by collaborations between the labs of the network. All of our ESR have contributed to outreach activities, interacting with a lay audience and the general public including children and adults of all ages and many nationalities.

The 4 scientific work packages (wp) led to the production of interesting and informative research data with the 15 ESR having worked on different aspects ranging from understanding fundamental biological mechanisms of Anaplastic Lymphoma Kinase (ALK)-induced lymphomagenesis (wp1) through to mechanisms of disease resistance (wp4). Specifically, within wp1 and 2 both genetic and epigenetic events as a consequence of aberrant ALK activity have been explored. Under wp3, novel therapeutic approaches were explored ranging from tumour vaccination through to combinatorial activities of novel targeted agents. It has been possible to show that children with ALCL develop a CD4+ T cell specific immune response to ALK and the mechanisms of this are under further investigation. We have also developed a commercial assay to detect circulating antibodies to ALK in patient's peripheral blood in collaboration with our partner organisation Cambridge Life Sciences. Additionally, the effects of co-treatment of ALCL with immune checkpoint inhibitors and ALK inhibitors has been investigated with promising results of relevance to the future treatment of patients. Finally, in wp4, the novel ALK inhibitor TPX-0005 has been assessed for its ability to inhibit the growth of ALK-addicted neuroblastoma cell lines and this activity will continue to determine its effects against numerous mutant forms of ALK.

Overall, the ALKATRAS project has fulfilled its aims and goals not only having trained 15 ESR but also producing important research findings with clinical applications and disseminating this research to both professional and lay audiences.
The Early Stage Researchers (ESR) of the ALKATRAS programme all made significant progress in their research activities and have developed promising data for further exploration. In particular, our combined research activities involving representatives from paediatric and adult oncology, fundamental scientists and industry are together making significant progress in furthering our understanding of cancers driven by the aberrant expression of a protein called Anaplastic Lymphoma Kinase (ALK). In particular, as well as improving our understanding of the mechanisms of these diseases, we are making significant headway in developing novel therapeutics and disease biomarkers that will inform on the future management of these patients, a process aided by the inclusion of clinical oncologists holding key positions in clinical trial groups within Europe. Of note, a commercial assay has been developed to detect circulating ALK antibodies in patient serum which will be applied as a predictive test that may facilitate the use of less toxic regimens; final stages of validation are currently underway. In addition, we are currently evaluating novel ALK inhibitors for their efficacy in the treatment of both naive and relapsed disease. As such, we have not only improved our understanding of how these diseases develop and occur but also better ways the treat them both at initial presentation and on relapse.
ESR of ALKATRAS at a training event in Brno, Czech Republic