Collaborating with individuals with lived experience to adapt CANMAT clinical depression guidelines into a patient treatment guide: The CHOICE-D co-design process.

Effective treatment of depression involves collaboration with informed patients and families and appropriate knowledge sharing. We describe here our experience, as a case example, of a collaboration to "translate" a clinical guideline designed for practitioners into an accessible, plainlanguage version that patients and families can use during the care process, both to provide basic educational information and to foster informed discussions with their treatment providers. Content experts in knowledge translation, patient advocacy, patient-oriented research, and psychiatry guided overall project design. Our first step was to identify lived experience writers to join in the codesign and co-writing of the "CHOICE-D Patient and Family Guide to Depression Treatment." A national call for writers attracted 62 applicants, from whom eight individuals with lived experience of depression and writing experience were selected. Individuals subsequently attended a welcoming teleconference, followed by a 1-day workshop designed to provide (a) a detailed overview of the clinician guideline, (b) an opportunity to select what should be included in the Guide, and (c) key principles of knowledge translation/lay writing. Both from the workshop and subsequently through the codesign process, lived experience writers recommended that the Guide address symptoms, effects of illness course on treatment, first-line treatments, safety/side effects, and treatment misconceptions. To promote patient autonomy, question scripts (how and what to ask your treatment provider), self-triaging resources, and treatment selection aids were suggested. Stylistic considerations included use of simple yet hopeful language, brevity, white space, key terms glossary, and graphics. Several strategies were particularly useful to optimize writer engagement in the codesign process: a pre-workshop conference call and circulation of project resources, an in-person workshop to increase content knowledge, structured discussion with co-writers and project leads to develop ideas, and practical training exercises with the provision of feedback. Both during and at the end of the project, writers provided additional recommendations for improving the process, including more in-person meetings, distribution of step-by-step instructions on the writing task, and a key terms glossary of technical terms to support their role. In conclusion, we describe a process with practical tips and reflective feedback on important considerations for engaging persons with lived experience as leaders in the codesign and writing process of lay treatment guidelines. These methods may serve as a model for similar projects in other areas of healthcare.

Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death.

The mevalonate (MVA) pathway is often dysregulated or overexpressed in many cancers suggesting tumor dependency on this classic metabolic pathway. Statins, which target the rate-limiting enzyme of this pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), are promising agents currently being evaluated in clinical trials for anti-cancer efficacy. To uncover novel targets that potentiate statin-induced apoptosis when knocked down, we carried out a pooled genome-wide short hairpin RNA (shRNA) screen. Genes of the MVA pathway were amongst the top-scoring targets, including sterol regulatory element binding transcription factor 2 (SREBP2), 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) and geranylgeranyl diphosphate synthase 1 (GGPS1). Each gene was independently validated and shown to significantly sensitize A549 cells to statin-induced apoptosis when knocked down. SREBP2 knockdown in lung and breast cancer cells completely abrogated the fluvastatin-induced upregulation of sterol-responsive genes HMGCR and HMGCS1. Knockdown of SREBP2 alone did not affect three-dimensional growth of lung and breast cancer cells, yet in combination with fluvastatin cell growth was disrupted. Taken together, these results show that directly targeting multiple levels of the MVA pathway, including blocking the sterol-feedback loop initiated by statin treatment, is an effective and targetable anti-tumor strategy.

Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop.

New therapies are urgently needed for hematologic malignancies, especially in patients with relapsed acute myelogenous leukemia (AML) and multiple myeloma. We and others have previously shown that FDA-approved statins, which are used to control hypercholesterolemia and target the mevalonate pathway (MVA), can trigger tumor-selective apoptosis. Our goal was to identify other FDA-approved drugs that synergize with statins to further enhance the anticancer activity of statins in vivo. Using a screen composed of other FDA approved drugs, we identified dipyridamole, used for the prevention of cerebral ischemia, as a potentiator of statin anticancer activity. The statin-dipyridamole combination was synergistic and induced apoptosis in multiple myeloma and AML cell lines and primary patient samples, whereas normal peripheral blood mononuclear cells were not affected. This novel combination also decreased tumor growth in vivo. Statins block HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the MVA pathway. Dipyridamole blunted the feedback response, which upregulates HMGCR and HMG-CoA synthase 1 (HMGCS1) following statin treatment. We further show that dipyridamole inhibited the cleavage of the transcription factor required for this feedback regulation, sterol regulatory element-binding transcription factor 2 (SREBF2, SREBP2). Simultaneously targeting the MVA pathway and its restorative feedback loop is preclinically effective against hematologic malignancies. This work provides strong evidence for the immediate evaluation of this novel combination of FDA-approved drugs in clinical trials.