Promoting lung cancer screening of high-risk patients by primary care providers.

BACKGROUND: Lung cancer screening (LCS) with low-dose computed tomography (LDCT) of the chest of eligible patients remains low. Accordingly, augmentation of appropriate LCS referrals by primary care providers (PCPs) was sought. METHODS: The quality improvement (QI) project was performed between April 2021 and June 2022. It incorporated patient education, shared decision-making (SDM) with PCPs, and tracking of initial LDCT completion. In each case, lag time (LT) to LCS and pack-years (PYs) were calculated from initial LCS eligibility. The cohort's scores were compared to national scores. Patient zip codes were used to create a geographic map of our cohort for comparison with public health data. RESULTS: An immediate and sustained increase in weekly LCS referrals from PCPs was recorded. Of 337 initial referrals, 95% were men, consisting of 66.2% Black, 28.4% White, and 5.4% other. Mean PY was less for minorities (45.3 vs. 37.3 years; p = .0002) but mean LT was greater for Whites (7.9 vs. 6.2 years; p = .03). Twenty-five percent of veterans failed to report to their scheduled screening, and two declined referrals. Notably, most no-show patients lived in transit deserts. Furthermore, Lung-RADS scores 4B/4X were more than double the expected prevalence (p = .008). CONCLUSIONS: The PCPs in this study successfully augmented LCS referrals. A substantial proportion of these patients were no-shows, and our data suggest complex racial and socioeconomic factors as contributing variables. In addition, a higher-than-expected number of initial Lung-RADS scores 4B/4X were reported. A large, multisite QI project is warranted to address overcoming potential transportation barriers in high-risk patient populations.

Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms.

Interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and also directly inhibit tumor growth. IFNα is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFNα and others do not. Here, we identify and characterize a pathway involving PKCδ-dependent phosphorylation of ULK1 on serine residues 341 and 495, required for subsequent activation of p38 MAPK. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from MPN patients, and that increased levels of ULK1 and p38 MAPK correlate with clinical response to IFNα therapy in these patients. We also demonstrate that IFNα treatment induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vitro and in vivo, triggering a negative feedback loop that suppresses IFN responses. Overexpression of ROCK1/2 is seen in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid precursors from MPN patients. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPNs.

Dual targeting of acute myeloid leukemia progenitors by catalytic mTOR inhibition and blockade of the p110α subunit of PI3 kinase.

The mammalian target of rapamycin (mTOR) and phosphoinositide-3-kinase (PI3K) pathways are often aberrantly activated in acute myeloid leukemia (AML) and play critical roles in proliferation and survival of leukemia cells. We provide evidence that simultaneous targeting of mTOR complexes with the catalytic mTOR inhibitor OSI-027 and of the p110α subunit of PI3K with the specific inhibitor BYL-719 results in efficient suppression of effector pathways and enhanced induction of apoptosis of leukemia cells. Importantly, such a combined targeting approach results in enhanced suppression of primitive leukemic progenitors from patients with AML. Taken together, these findings raise the possibility of combination treatments of mTOR and p110α inhibitors as a unique approach to enhance responses in refractory AML.

Autophagy is a survival mechanism of acute myelogenous leukemia precursors during dual mTORC2/mTORC1 targeting.

PURPOSE: To examine whether induction of autophagy is a mechanism of leukemic cell resistance to dual mTORC1/mTORC2 inhibitors in acute myelogenous leukemia (AML) leukemic progenitors. EXPERIMENTAL DESIGN: Combinations of different experimental approaches were used to assess induction of autophagy, including immunoblotting to detect effects on LC3II and p62/SQTM1 expression and on ULK1 phosphorylation, immunofluorescence, and electron microscopy. Functional responses were assessed using cell viability and apoptosis assays, and clonogenic leukemic progenitor assays in methylcellulose. RESULTS: We provide evidence that treatment of AML cells with catalytic mTOR inhibitors results in induction of autophagy, which acts as a regulatory mechanism to promote leukemic cell survival. Such induction of autophagy by dual mTORC1/mTORC2 inhibitors partially protects primitive leukemic precursors from the inhibitory effects of such agents and limits their activities. Simultaneous blockade of the autophagic process using chloroquine or by knockdown of ULK1 results in enhanced antileukemic responses. CONCLUSIONS: Dual targeting of mTORC2 and mTORC1 results in induction of autophagy in AML cells. Combinations of catalytic mTOR targeting agents and autophagy inhibitors may provide a unique approach to target primitive leukemic precursors in AML.