AACR 2016

Dr Xose Puente speaks with ecancertv at AACR2016 about his discoveries of mutations in non-coding regions driving tumourigensis in chronic lymphocytic leukaemia. Using a library of genomic data from CLL patients, Dr Puente's lab were able to determine point mutations outside of the coding regions of patients DNA that gave rise to altered gene expression. A single substitution in the 3' tail of Notch1, a cell cycle regulator, is reported as introducing a novel splicing site resulting in the deletion of 500 base pairs, including those which determine Notch1 persistence in healthy cells. Another mutation in an intragenic region results in down-regulation of Pax5, essential for B cell maturation. These results are among the first to indicate the clinical significance of non-coding DNA to cancer development.

Dr Martine Piccart presents at AACR 2016 about the results of the MINDACT trial. Using a new diagnostic assay, Mammaprint, to scan for a 70 gene signature, Dr Piccart reports significant predictive potential for determining breast cancer relapse risk.

Dr Robert Gillies talks to ecancertv at AACR 2016 about novel imaging techniques in tumour habitats. Considering the stalling durable response rate of many targeted-therapy patients due to tumour evolution, Dr Gillies discusses the value of multiple imaging techniques to determining tumour habitat and response potential. He also discusses the impact of data libraries on treating patients with regard to understanding tumour biology and heterogeneity.

Dr Xuehong Zhang presents his research at AACR 2016 on risk prediction models, of critical importance to patients evaluating their treatment options, and how to improve the prognostic accuracy of existing models based on novel biomarkers. Dr Zhangs' modified models proved informative to patients and effective in shaping treatment decisions, especially for postmenopausal women not using hormone therapy (HT).

Dr Lindsay Morton presents results at AACR 2016 on the risk childhood cancer patients face of developing breast cancer later in life. With a growing population of long-lived cancer survivors, Dr Morton has led investigations into the susceptibility of patients to secondary malignancies in the years following their initial treatment.

Dr Philip Low speaks with ecancertv at AACR 2016 about a novel technique to selectively identify tumour cells in vivo. With potentially toxic side effects to uncontrolled tumour lysis and hard-to-target heterogeneity, Dr Low describes a new method of using fluorescein dye to bridge tumours and T Cells. By controlling administration rate and relying on large tumour-ligand libraries currently available, Dr Low reports significant tumour reduction at a low cost. In adjacent human clinical trials, fluorescein dye binding to tumours has also improved tumour visibility and specificity in surgery.

Dr Rafaella Sordella speaks with ecancertv at AACR 2016 about cell plasticity affecting its susceptibility to therapies. With specific regard to non-genetic mechanisms of resistance in cancer cells, Dr Sordella explains the flexible cell state, how some cells persist and respond to therapies, and how targeting this malleability might influence future treatment. Speaking about the conference, Dr Sordella also reflects on the benefits to clinicians and patients alike gained through open exchange of information and understanding between different fields of biology.

Dr Angela deMichele presents results at AACR 2016 from the ISPY2 trial, a novel trial design architecture to determine new drug therapies for patients with Her2 breast cancer, and to pair patients with the most effective possible treatment. From this arm, she reports significant improvement among patients receiving TDM1 with pertuzumab compared to current therapies.

Dr Paul Nghiem speaks with ecancertv at AACR 2016 about his research to treat MCC, a virally induced cancer, using pembrolizumab. The Merkel cell polyoma virus can inhabit human skin, infecting a site in childhood and not become pathogenic until decades later, leading to Dr Nghiem describing the likelihood that its reawakening is caused by immune quiescence in later age. Reversing this immune suppression with pembrolizumab is reported as an effective treatment, and helps to re-established host immunity as potent even after the age of 65.

Dr Noriyuki Kasahara speaks with ecancertv at AACR2016 about his cancer-targeting retroviral therapies which illicit host immune responses. Historically, oncolytic viruses have struggled to compete with host immunity to reach their target and the immunosuppresive tumour environment. But by using a retroviral factor, Dr Kasahara's lab reports selective targeting of cancer cells with a gene primer that in turn responds to a non-toxic pro-drug to kill the 'infected' tumour cells. Dr Kasahara reports significant extension to patient survival compared to current chemotherapy treatments, with no systemic toxicity and high-tumour specificity. Trials are ongoing.

Dr Nancy Davidson speaks with ecancertv at AACR 2016 about recent news in breast cancer treatment. Addressing the research presented by Dr Piccart, Dr Morton, Dr deMichele and the work of Dr Xuehong Zhang to improve patient risk prediction via biomarkers, Dr Davidson summarises the themes and goals of AACR.

Dr Nicholas McGranahan talks with ecancertv at AACR 2016 about tumour heterogeneity and mutational markers for immunotherapy. Within tumours, mutations can give rise to varying gene expression that in turn effects the potential efficacy of a targeted treatment. However, each mutation may in turn give rise to a presented peptide that could be recognised by a patients innate immunity. Rather than the specific mutational drivers of cancer, Dr McGranahan reports on the targeting of these neoantigens as non-self markers, a highly personalised target for potential therapies.

Dr Martine Piccart speaks with ecancertv at AACR 2016 about the results of the MINDACT trial. Using a new diagnostic assay, Mammaprint, to scan for a 70 gene signature, Dr Piccart reports significant predictive potential for determining breast cancer relapse risk. With breast cancer being knowingly over-treated, the results from this trial enable the reduction of unnecessary treatments, even in patients classified as high risk via Adjuvant!Online, and lead to strategic de-escalation of chemotherapy.

Dr Kunle Odunsi talks to ecancertv at AACR 2016 about his research into courses of immunotherapy against ovarian cancer. Having established in previous research the link between T cell infiltration of a tumour to improved patient survival, Dr Odunsi has sought to determine an ovarian cancer antigen - in this case NY-ESO-1 - to prolong patient remission and promote anti-tumour immune response in patients. Historically, cancer cells have evaded immune response via manipulation of cellular checkpoints PD1 and IDO, which limits T cell proliferation. By combining these targets with CAR-T cell technologies, Dr Odunsi hopes to extend T cell lifespans in patients, and provide a long-lasting anti-tumour effector T cell population.

Dr Marianne Ratcliffe speaks with ecancertv at AACR 2016 about her work in establishing the comparative efficacy of three commercially available PDL-1 assays. With pembrolizumab gaining increasing traction as a therapy across an array of cancer types, many different assays are available from multiple manufacturers but with little data available on their interchangability. Dr Ratcliffe reports a high degree of concordance between three assays, and highlights the ongoing debate of using PDL-1 positive or negative results to influence patient medication as an area requiring further consideration with hopes to reach a broad agreement of test suitability.

Dr Lindsay Morton speaks with ecancertv at AACR2016 about the risk childhood cancer patients face of developing breast cancer later in life. With a growing population of long-lived cancer survivors, Dr Morton has led investigations into the susceptibility of patients to secondary malignancies in the years following their initial treatment. Dr Morton highlights that this is only a discovery study, and that childhood survival of primary malignancies without relapse is overall a success story, to which clinicians are only now discovering downstream risks.

Prof Jorge Moscat speaks with ecancertv at AACR 2016 about signalling pathways involving p62. He describes the role of p62-regulated detoxification, and how this can be subverted to promote cancer cell survival and proliferation. Currently his work focuses on molecular targeting of p62, which has prevented hepatocarcinoma in mouse models.

Dr Luis Parada talks with ecancertv at AACR 2016 about his research into the origins of cancer. Rather than the threat of any cell spontaneously becoming cancerous, Dr Parada reports that only stem or progenitor cells have the potential to initialise oncogenesis. Using the example of his adjacent research into neurofibromatosis, he describes the need to identify and target cancer stem cells to assure full remission.

Professor Irving L Weissman talks to ecancertv at AACR 2016 about his labs research into immune evasion of cancer cells. Calreticulin, which is normally down-regulated by stem cells transiting between bone marrow sites, is also blocked from the surface of cancer stem cells to prevent immune recognition. Normally, calreticulin acts as an “eat me signal” to macrophages, and by producing a humanised antibody towards it in treating leukaemia and solid tumours, Prof Weissman hopes to combine it with immunotherapeutics and recruit an immune response.

Dr Jayesh Desai speaks with ecancertv at AACR 2016 about his phase Ia trial with RAF-dimer inhibitor BGB283. BGB283 also acts an EGFR inhibitor, and may have effect on downstream RAS expression. Dr Desai's trial reports results from numerous tumour types from patients all expressing RAF/BRAF mutations, using BGB283 as a single agent.

Dr Ilaria Malanchi speaks with ecancertv at AACR 2016 about her research into immune response to metastasis. She describes how metastatic success of cancer cells can be attributed to Thrombospondin 2 (THBS2), a factor triggering the development of a metastatic niche. While tumour detection by a host immune system can illicit a systemic response, metastatic spread to other tissues results in a leukotriene-mediated inflammatory response that in turn accelerates infiltration further. Dr Malanchi describes her research to block this inflammatory pathway using medicine currently available for asthma, and looks forwards to the development of a comprehensive THBS2 strategy.

Dr David Hong speaks with ecancertv at AACR 2016 with updated results targeting TRK fusions with LOXO101. NTRK, normally associated with the sense of touch, can fuse and become oncogenic in a variety of tumour histologies. LOXO101 is described as the first selective inhibitor of TRKa, b and c, compared to the more generalised entrectinib, which Dr Hong reports as assuring greater specificity and thus lower offtarget effects. A Phase II trial is ongoing.

Dr Kenneth Anderson meets with ecancertv at AACR 2016 to discuss the past, present and future of myeloma treatment. Myeloma treatments have benefitted from immunotherapeutic developments in recent years, with survival and quality of life rising across many diseases. With specific attention to checkpoint inhibitor PDL-1, Dr Anderson summarises the roles and applications of different immune cell types, even approaching an innate anti-tumour response.

Dr Leisha Emmens speaks with ecancertv at AACR 2016 about her efforts to shape a course of immunotherapy against, what were previously considered non-immunogenic, breast cancers. Having identified efficacy of a moderate dose of cyclophosphamide via combination therapy in previous studies, Dr Emmens is now moving forwards with trials of trastuzumab combination therapies for metastatic disease. Looking forward, she describes her hopes for immunotherapy to offer effective, personalised treatment to all patients and all tumour types.

Dr Paul Tumeh speaks with ecancertv at AACR 2016 about determining potential biomarkers using multiplexed immunohistochemistry. Having created a spatially resolved model of the tumour microenvironment in all its heterogeneity, with different cell types identified by coloured labels, Dr Tumeh describes visible tracking of a tumour responding to immunotherapy. As such, he explains how multiple biomarkers are a necessary course for increased drug efficacy, and that a negative assay response to one biomarker need not be a prognostic limitation.

Dr Nada Jabado speaks with ecancertv at AACR 2016 about epigenetic mutations found in high grade gliomas. Single nucleotide polymorphisms that occur within the epigenome can alter the structural assembly of proteins and the function of cellular components, with Dr Jabado reporting on a handful of mutations that can alter cell architecture, resulting in a pluripotent and resistant cancer. She also describes the incidence of ependymoma, apparently not characterised by mutational origin, but a structural malformation that results in high mortality.

Dr Stephen Hodi presents results at AACR 2016, following up on five year survival rates of metastatic melanoma patients who had received nivolumab. He reports that the number of patients surviving beyond the five year mark is double that of treatment in years before nivolumab was available (34% v 16.6% 2005-2011)

Dr Riccardo Dalla-Favera speaks with ecancertv at AACR 2016 about the processes by which tumours evade immune detection. By either sequestering cell surface antigens or subverting checkpoint regulators of cell death, tumours are able to persist within a host and encounter no immune resistance. Dr Dalla-Favera summarises current research in reawakening a patients immune system, and describes the therapeutic possibilities of directed T cell therapy.

Dr Alexander Drilon presents his research on entrectinib in a press release at AACR 2016. Entrectinib, which targets the proteins TrkA/B/C, ROS1, and ALK, is reported as safe, tolerable, and showing signs of clinical activity in patients who had several different types of cancer with associated gene alterations.

Dr Shivaani Kummar speaks with ecancertv at AACR 2016 about cell cycle regulation by checkpoint inhibitors. By utilising the same checkpoint mechanisms that prevent damaged cells from replicating to limit tumour growth and stimulate host immunity, Dr Kummar describes the clinical significance of targeting Wee1 kinase pathways. With trials of combination therapies and single agents now entering phase II, she also reports on the toxic side effects and risks of adjacent cytotoxic therapies.

Dr John Bushweller speaks with ecancertv at AACR 2016 about his efforts to target transcription factors as cancer therapy. Transcription factors have historically been too transient to effectively control gene expression in tumour cells, but Dr Bushweller describes a novel technique to inhibit transcription factor fusion that has resulted in restoring normal gene expression to cells. Gene alteration in situ is itself a hallmark of tumourigenesis, and Dr Bushweller reports that combination with activated kinase therapy may be able to limit cancer mutagenesis.

Dr Sergei Grivennikov speaks with ecancertv at AACR 2016 on the mechanisms by which a tumour can modulate its environment to promote inflammation for its own benefit. Normally an immune response to infection, tumour upregulation of the inflamed environment attracts cell repair and growth factors that would otherwise heal a wound, contributing to further cancer growth. Dr Grivennikov reviews different therapeutic prospects in treating cancer by destabilising the microenvironment, from aspirin to targeted molecules.

Dr Ying Wang speaks with ecancertv at AACR 2016 about the impact of regular low-impact exercise on patient prognosis in prostate cancer. Patient survival has been related to physical exercise in previous research, and Dr Wang reports on the associations relating to prostate cancer, considering the potential influence of post-diagnosis decline and the risks associated with time spent sat down.

Dr Yong-Chen William Lu speaks with ecancertv at AACR 2016 about a phase I study of using CD4 T cells in therapy. Often described as 'helper T Cells', CD4 T cells used by Dr Lu helped safely target cancer cells in trial patients and stimulate anti-tumour responses. He also introduces his ongoing work with MAGE-A3, a cancer gemini antigen that exists only in tumour cells and undifferentiated cells, as a promising target in further trials.

Dr Yong-Chen William Lu presents his results at AACR 2016 from a phase I study of using CD4 T cells in therapy. Often described as 'helper T Cells', CD4 T cells used by Dr Lu helped safely target cancer cells in trial patients and stimulate anti-tumour responses.

Dr Aaron Logan speaks with ecancertv at AACR 2016 about developments in determining the levels of residual disease presence in patients following treatment. He reports that, utilising the molecular techniques becoming available, detecting the signs of a patient's deep disease response are an effective predictor of disease free survival. With novel technologies becoming standardised techniques, the ability to determine a patients cancer clonotype and search for its remission in greater detail than light microscopy alone may make it possible to improve screening, therapy, and response duration.

Dr Andrea Califano speaks with ecancertv at AACR 2016 to summarise recent developments in cancer research and advances in checkpoint research. From past therapies to modern immunotherapy, Dr Califano looks forward to the next potential steps in cancer management; mechanistic targets, tumour checkpoints and cell regulators. By developing comprehensive models of cell behaviours with which to forecast drug efficacy and identify oncogenic sources, he describes the potential of near-future therapies to single out the root causes of cancer, before they manifest as malignancies.

Dr Angela deMichele speaks with ecancertv at AACR 2016 about the results of the ISPY2 trial to determine new drug therapies for patients with HER2 positive breast cancer. From this arm, she reports significant improvement among patients receiving TDM1 with pertuzumab compared to current therapies. With this success in mind, she discusses the novel design of the ISPY2 trial, which accelerates patients towards more successful schemes to improve drug design and reduce toxicity, and its possible applications across the sector.

Dr Yu Shyr speaks with ecancertv at AACR 2016 about the potential applications of sequencing data libraries. Faced with a vast wealth of genomic information, Dr Shyr sets out a strategy for training and incorporation of data science into trial design and outcomes. With all this information in mind, he also makes note of the need for genetic counselling for patients, and for the field as a whole to match the speed and responsiveness of other industries.

Dr Barry Berger speaks with ecancertv at AACR 2016 about response rates to Cologuard, which tests patient stool samples for DNA (S-DNA) indicative of colorectal cancer. With a high response rate among previously reluctant patients, he describes the benefits to patients and clinicians of a non-invasive test which can also indicate pre-cancerous lesions.

Dr Brian Ruffell speaks with ecancertv at AACR 2016 about his work with mouse models of myeloid cells. Focussing on the macrophage receptor to CSF1, he discusses cell plasticity between patients, sites and stress conditions.

Dr Christin Burd speaks with ecancertv at AACR 2016 about her research into the potential for SPF30 sunscreen to delay the onset of melanoma. Though the damaging potential of UVA and UVB radiation has long been known, attitudes in the cosmetic industry (which regulates sun-screen lotion development) are at odds with the animal testing required to prove a direct delay of melanoma onset in UV sensitive knockout mice.