Faculty Bibliography

Introduction: Myeloproliferative neoplasms (MPN) are myeloid malignancies with somatic JAK2, CALR or MPL mutations and constitutive activation of JAK2 signaling. JAK2 inhibitors show limited efficacy due to residual MAPK pathway activation. The molecular connection of JAK2 and MAPK pathway in MPN is not fully clarified. We study the role of SHP2, a protein tyrosine phosphatase involved in MAPK activation in other tyrosine kinase- driven malignancies, and assess its therapeutic potential.
Method(s): SHP2 was depleted by shRNA induced knockdown in Ba/F3 cells stably expressing Jak2V617F or wildtype Jak2. For SHP2 inhibition TNO155 and IACS13909 were used. Translational potential of JAK2/SHP2 inhibition was studied in Jak2V617F and MPLW515L mouse models.
Result(s): SHP2 was expressed at substantial levels in MPN cells including SET2, UKE-1 and Jak2V617F Ba/F3 cells. SHP2 knockdown reduced activation of MAPK pathway kinases including MEK, ERK and RSK as well as MAPK downstream effectors as DUSP6. SHP2 i nhibition w ith TNO155 o r I ACS-13909 analogously interfered with MAPK activation and effector expression and effects were most pronounced when JAK2 inhibition by ruxolitinib and SHP2 inhibition were combined (A). MPN cell proliferation was inhibited at significantly lower IC50 when combining ruxolitinib with TNO155 or IACS-13909 compared to ruxolitinib as single agent (B). Since inhibition of wildtype haematopoiesis is a concern, anti-proliferative activity of JAK2/SHP2 inhibition was assessed in cells with wildtype Jak2, which showed more modest inhibition (C). In a Jak2V617F mouse model, the SHP2 inhibitor TNO155 mediated corrective effects on MPN phenotype including splenomegaly, erythrocytosis and leucocytosis within a week. Of note, TNO155 as single agent showed similar effects as ruxolitinib at tolerable doses, while combined JAK2/SHP2 inhibition enhanced efficacy. In a MPLW515L mouse model with extensive leucocytosis, JAK2/SHP2 inhibitor treatment promptly normalized leukocyte counts which is not seen to this extent with ruxolitinib (D-E).
Conclusion(s): Our f indings suggest a s ignificant role of SHP2 function in MPN given enhanced MAPK suppression and corrective effects upon SHP2 targeting in MPN models. Further studies will delineate the involvement of phosphatase vs. nonphosphatase functions and address the potential of JAK2/SHP2 inhibition as therapeutic approach in MPN. (Figure Presented)

OBJECTIVES/OBJECTIVE:Behavioral health diagnoses are frequently underreported in administrative health data. For a pragmatic trial of a hospital addiction consult program, we sought to determine the sensitivity of Medicaid claims data for identifying patients with opioid use disorder (OUD). METHODS:A structured review of electronic health record (EHR) data was conducted to identify patients with OUD in 6 New York City public hospitals. Cases selected for review were adults admitted to medical/surgical inpatient units who received methadone or sublingual buprenorphine in the hospital. For cases with OUD based on EHR review, we searched for the hospitalization in Medicaid claims data and examined International Classification of Diseases, Tenth Revision discharge diagnosis codes to identify opioid diagnoses (OUD, opioid poisoning, or opioid-related adverse events). Sensitivity of Medicaid claims data for capturing OUD hospitalizations was calculated using EHR review findings as the reference standard measure. RESULTS:Among 552 cases with OUD based on EHR review, 465 (84.2%) were found in the Medicaid claims data, of which 418 (89.9%) had an opioid discharge diagnosis. Opioid diagnoses were the primary diagnosis in 49 cases (11.7%), whereas in the remainder, they were secondary diagnoses. CONCLUSION/CONCLUSIONS:In this sample of hospitalized patients receiving OUD medications, Medicaid claims seem to have good sensitivity for capturing opioid diagnoses. Although the sensitivity of claims data may vary, it can potentially be a valuable source of information about OUD patients.

BACKGROUND:Evidence maps are emerging data visualization of a systematic review. There are no published evidence maps summarizing opioid use disorder (OUD) interventions. AIM/OBJECTIVE:Our aim was to publish an interactive summary of all peer-reviewed interventional and observational trials assessing the treatment of OUD and common clinical outcomes. METHODS:PubMed, Embase, PsycInfo, Cochrane Central Register of Clinical Trials, and Web of Science were queried using multiple OUD-related MESH terms, without date limitations, for English-language publications. Inclusions were human subjects, treatment of OUD, OUD patient or community-level outcomes, and systematic reviews of OUD interventions. Exclusions were laboratory studies, reviews, and case reports. Two reviewers independently scanned abstracts for inclusion before coding eligible full-text articles by pre-specified filters: research design, study population, study setting, intervention, outcomes, sample size, study duration, geographical region, and funding sources. RESULTS:The OUD Evidence Map (https://med.nyu.edu/research/lee-lab/research/opioid-use-disorder-treatment-evidence-map) identified and assessed 12,933 relevant abstracts through 2020. We excluded 9455 abstracts and full text reviewed 2839 manuscripts; 888 were excluded, 1591 were included in the final evidence map. The most studied OUD interventions were methadone (n = 754 studies), buprenorphine (n = 499), and naltrexone (n = 134). The most common outcomes were heroin/opioid use (n = 708), treatment retention (n = 557), and non-opioid drug use (n = 368). Clear gaps included a wider array of opioid agonists for treatment, digital behavioral interventions, studies of OUD treatments in criminal justice settings, and overdose as a clinical outcome. CONCLUSION/CONCLUSIONS:This OUD Evidence Map highlights the importance of pharmacologic interventions for OUD and reductions in opioid use. Future iterations will update results annually and scan policy-level interventions.

Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered 'undruggable' owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRAS^G12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.

BACKGROUND:There is pressing need to improve hospital-based addiction care. Various models for integrating substance use disorder care into hospital settings exist, but there is no framework for describing, selecting, or comparing models. We sought to fill that gap by constructing a taxonomy of hospital-based addiction care models based on scoping literature review and key informant interviews. METHODS:Methods included a scoping review of the literature on US hospital-based addiction care models and interventions for adults, published between January 2000 and July 2021. We conducted semi-structured interviews with 15 key informants experienced in leading, implementing, evaluating, andpracticing hospital-based addiction care to explore model characteristics, including their perceived strengths, limitations, and implementation considerations. We synthesized findings from the literature review and interviews to construct a taxonomy of model types. RESULTS:Searches identified 2,849 unique abstracts. Of these, we reviewed 280 full text articles, of which 76 were included in the final review. We added 8 references from reference lists and informant interviews, and 4 gray literature sources. We identified six distinct hospital-based addiction care models. Those classified as addiction consult models include (1) interprofessional addiction consult services, (2) psychiatry consult liaison services, and (3) individual consultant models. Those classified as practice-based models, wherein general hospital staff integrate addiction care into usual practice, include (4) hospital-based opioid treatment and (5) hospital-based alcohol treatment. The final type was (6) community-based in-reach, wherein community providers deliver care. Models vary in their target patient population, staffing, and core clinical and systems change activities. Limitations include that some models have overlapping characteristics and variable ways of delivering core components. DISCUSSION/CONCLUSIONS:A taxonomy provides hospital clinicians and administrators, researchers, and policy-makers with a framework to describe, compare, and select models for implementing hospital-based addiction care and measure outcomes.

OBJECTIVE:Polysubstance use may complicate treatment outcomes for individuals who use opioids. This research aimed to examine the prevalence of polysubstance use in an opioid use disorder treatment trial population and polysubstance use's association with opioid relapse and craving. METHODS:This study is a secondary data analysis of individuals with opioid use disorder who received at least one dose of medication (n = 474) as part of a 24-week, multi-site, open label, randomized Clinical Trials Network study (CTN0051, X:BOT) comparing the effectiveness of extended-release naltrexone versus buprenorphine. Models examined pretreatment polysubstance use and polysubstance use during the initial 4 weeks of treatment on outcomes of relapse by week 24 of the treatment trial and opioid craving. RESULTS:Polysubstance use was generally not associated with treatment outcomes of opioid relapse and craving. Proportion of days of pretreatment sedative use was associated with increased likelihood of opioid relapse (OR: 1.01, 95 % CI: 1.00-1.02). Proportion of days of cocaine use during the initial 4 weeks of treatment was associated with increased likelihood of opioid relapse (OR: 1.05, 95 % CI: 1.01-1.09) but this effect was no longer significant once the potential of confounding by opioid use was considered. Sedative use during initial 4 weeks of treatment was associated with increased opioid craving (b: 0.77, 95 % CI: 0.01-1.52). The study found no other significant relationships. CONCLUSIONS:In the current study population, polysubstance use was only marginally associated with 24-week treatment outcomes.

The United States is experiencing an unprecedented opioid crisis, with a record of about 93,000 opioid-involved overdose deaths in 2020, which requires rapid and substantial scaling up of access to effective treatment for opioid use disorder. Only 18% of individuals with opioid use disorder receive evidence-based treatment, and strategies to increase access are hindered by a lack of treatment providers. Using a case study from the largest municipal hospital system in the United States, the authors describe the effects of a workforce shortage on health system responses to the opioid crisis. This national problem demands a multipronged approach, including federal programs to grow and diversify the pipeline of addiction providers, medical education initiatives, and enhanced training and mentorship to increase the capacity of allied clinicians to treat patients who have an opioid use disorder. Workforce development should be combined with structural reforms for integrating addiction treatment into mainstream medical care and with new treatment models, including telehealth, which can lower patient barriers to accessing treatment.

Single-nucleotide polymorphisms (SNPs) in RNF213, which encodes a 591-kD protein with AAA+ ATPase and RING E3 domains, are associated with a rare, autosomal dominant cerebrovascular disorder, moyamoya disease (MMD). MMD-associated SNPs primarily localize to the C-terminal region of RNF213, and some affect conserved residues in the RING domain. Although the autosomal dominant inheritance of MMD could most easily explained by RNF213 gain-of-function, the type of ubiquitylation catalyzed by RNF213 and the effects of MMD-associated SNPs on its E3 ligase activity have remained unclear. We found that RNF213 uses the E2-conjugating enzymes UBE2D2 and UBE2L3 to catalyze distinct ubiquitylation events. RNF213-UBED2 catalyzes K6 and, to a lesser extent, K48-dependent poly-ubiquitylation in vitro, whereas RNF213-UBE2L3 catalyzes K6-, K11-, and K48-dependent poly-ubiquitylation events. MMD-associated SNPs encode proteins with decreased E3 activity, and the most frequent MMD allele, RNF213

Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single cell RNA-sequencing reveal that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting show that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation.