Katharina Rothe

Precision autophagy: Will the next wave of selective autophagy markers and specific autophagy inhibitors feed clinical pipelines?

Research presented at the Vancouver Autophagy Symposium (VAS) 2014 suggests that autophagys influence on health and disease depends on tight regulation and precision targeting of substrates. Discussions recognized a pressing need for robust biomarkers that accurately assess the clinical utility of modulating autophagy in disease contexts. Biomarker discovery could flow from investigations of context-dependent triggers, sensors, and adaptors that tailor the autophagy machinery to achieve target specificity. In his keynote address, Dr. Vojo Deretic (University of New Mexico) described the discovery of a cargo receptor family that utilizes peptide motif-based cargo recognition, a mechanism that may be more precise than generic substrate tagging. The keynote by Dr. Alec Kimmelman (Harvard Medical School) emphasized that unbiased screens for novel selective autophagy factors may accelerate the development of autophagy-based therapies. Using a quantitative proteomics screen for de novo identification of autophagosome substrates in pancreatic cancer, Kimmelmans group discovered a new type of selective autophagy that regulates bioavailable iron. Additional presentations revealed novel autophagy regulators and receptors in metabolic diseases, proteinopathies, and cancer, and outlined the development of specific autophagy inhibitors and treatment regimens that combine autophagy modulation with anticancer therapies. VAS 2014 stimulated interdisciplinary discussions focused on the development of biomarkers, drugs, and preclinical models to facilitate clinical translation of key autophagy discoveries.

Autophagy: From structure to metabolism to therapeutic regulation

Multidisciplinary approaches are increasingly being used to elucidate the role of autophagy in health and disease and to harness it for therapeutic purposes. The broad range of topics included in the program of the Vancouver Autophagy Symposium (VAS) 2013 illustrated this multidisciplinarity: structural biology of Atg proteins, mechanisms of selective autophagy, in silico drug design targeting ATG proteins, strategies for drug screening, autophagy-metabolism interplay, and therapeutic approaches to modulate autophagy. VAS 2013 took place at the British Columbia Cancer Research Centre, and was hosted by the CIHR Team in Investigating Autophagy Proteins as Molecular Targets for Cancer Treatment. The program was designed as a day of research exchanges, featuring two invited keynote speakers, internationally recognized for their groundbreaking contributions in autophagy, Dr Ana Maria Cuervo (Albert Einstein College of Medicine, Bronx, NY) and Dr Jayanta Debnath (University of California, San Francisco). By bringing together international and local experts in cell biology, drug discovery, and clinical translation, the symposium facilitated rich interdisciplinary discussions focused on multiple forms of autophagy and their regulation and modulation in the context of cancer.Multidisciplinary approaches are increasingly being used to elucidate the role of autophagy in health and disease and to harness it for therapeutic purposes. The broad range of topics included in the program of the Vancouver Autophagy Symposium (VAS) 2013 illustrated this multidisciplinarity: structural biology of Atg proteins, mechanisms of selective autophagy, in silico drug design targeting ATG proteins, strategies for drug screening, autophagy-metabolism interplay, and therapeutic approaches to modulate autophagy. VAS 2013 took place at the British Columbia Cancer Research Centre, and was hosted by the CIHR Team in Investigating Autophagy Proteins as Molecular Targets for Cancer Treatment. The program was designed as a day of research exchanges, featuring two invited keynote speakers, internationally recognized for their groundbreaking contributions in autophagy, Dr Ana Maria Cuervo (Albert Einstein College of Medicine, Bronx, NY) and Dr Jayanta Debnath (University of California, San Francisco). By bringing together international and local experts in cell biology, drug discovery, and clinical translation, the symposium facilitated rich interdisciplinary discussions focused on multiple forms of autophagy and their regulation and modulation in the context of cancer.

PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL+ human leukemia

PP2A inhibitors and BCR-ABL inhibitors synergize to kill drug-insensitive leukemia cells. Drug pair enABLes killing of leukemia Imatinib, the classic targeted drug for the treatment of cancer, was designed to target the BCR-ABL fusion protein in chronic myeloid leukemia and has saved many patients’ lives. Unfortunately, some leukemias are resistant to imatinib despite having the BCR-ABL translocation, and others can develop resistance during treatment. Moreover, imatinib generally does not eradicate the leukemic stem cells and therefore requires continued treatment to maintain efficacy, so combination approaches are still needed. Lai et al. discovered that protein phosphatase 2A is a therapeutic target in imatinib-insensitive leukemia cells, including stem cells, and that the combination of imatinib and related drugs with PP2A inhibition effectively kills these cancer cells. Overcoming drug resistance and targeting leukemic stem cells (LSCs) remain major challenges in curing BCR-ABL+ human leukemia. Using an advanced drug/proliferation screen, we have uncovered a prosurvival role for protein phosphatase 2A (PP2A) in tyrosine kinase inhibitor (TKI)–insensitive leukemic cells, regulated by an Abelson helper integration site–1–mediated PP2A–β-catenin–BCR-ABL–JAK2 protein complex. Genetic and pharmacological inhibition of PP2A impairs survival of TKI nonresponder cells and sensitizes them to TKIs in vitro, inducing a dramatic loss of several key proteins, including β-catenin. We also demonstrate that the clinically validated PP2A inhibitors LB100 and LB102, in combination with TKIs, selectively eliminate treatment-naïve TKI-insensitive stem and progenitor cells, while sparing healthy counterparts. In addition, PP2A inhibitors and TKIs act synergistically to inhibit the growth of TKI-insensitive cells, as assessed by combination index analysis. The combination eliminates infiltrated BCR-ABL+ blast cells and drug-insensitive LSCs and confers a survival advantage in preclinical xenotransplant models. Thus, dual PP2A and BCR-ABL inhibition may be a valuable therapeutic strategy to synergistically target drug-insensitive LSCs that maintain minimal residual disease in patients.

CuboCube: Student creation of a cancer genetics e-textbook using open-access software for social learning

Student creation of educational materials has the capacity both to enhance learning and to decrease costs. Three successive honors-style classes of undergraduate students in a cancer genetics class worked with a new software system, CuboCube, to create an e-textbook. CuboCube is an open-source learning materials creation system designed to facilitate e-textbook development, with an ultimate goal of improving the social learning experience for students. Equipped with crowdsourcing capabilities, CuboCube provides intuitive tools for nontechnical and technical authors alike to create content together in a structured manner. The process of e-textbook development revealed both strengths and challenges of the approach, which can inform future efforts. Both the CuboCube platform and the Cancer Genetics E-textbook are freely available to the community.

Diverse mechanisms of autophagy dysregulation and their therapeutic implications: does the shoe fit?

ABSTRACT In its third edition, the Vancouver Autophagy Symposium presented a platform for vibrant discussion on the differential roles of macroautophagy/autophagy in disease. This one-day symposium was held at the BC Cancer Research Centre in Vancouver, BC, bringing together experts in cell biology, protein biochemistry and medicinal chemistry across several different disease models and model organisms. The Vancouver Autophagy Symposium featured 2 keynote speakers that are well known for their seminal contributions to autophagy research, Dr. David Rubinsztein (Cambridge Institute for Medical Research) and Dr. Kay F. Macleod (University of Chicago). Key discussions included the context-dependent roles and mechanisms of dysregulation of autophagy in diseases and the corresponding need to consider context-dependent autophagy modulation strategies. Additional highlights included the differential roles of bulk autophagy versus selective autophagy, novel autophagy regulators, and emerging chemical tools to study autophagy inhibition. Interdisciplinary discussions focused on addressing questions such as which stage of disease to target, which type of autophagy to target and which component to target for autophagy modulation. Abbreviations: AD: Alzheimer disease; AMFR/Gp78: autocrine motility factor receptor; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CML: chronic myeloid leukemia; CVB3: coxsackievirus B3; DRPLA: dentatorubral-pallidoluysian atrophy; ER: endoplasmic reticulum; ERAD: ER-associated degradation; FA: focal adhesion; HCQ: hydroxychloroquine; HD: Huntingtin disease; HIF1A/Hif1α: hypoxia inducible factor 1 subunit alpha; HTT: huntingtin; IM: imatinib mesylate; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; NBR1: neighbour of BRCA1; OGA: O-GlcNAcase; PDAC: pancreatic ductal adenocarcinoma; PLEKHM1: pleckstrin homology and RUN domain containing M1; polyQ: poly-glutamine; ROS: reactive oxygen species; RP: retinitis pigmentosa; SNAP29: synaptosome associated protein 29; SPCA3: spinocerebellar ataxia type 3; TNBC: triple-negative breast cancer.