Predictors of treatment initiation and mapping the cancer diagnostic pathway: A retrospective observational cohort study of patients with metastatic non-small cell lung cancer.

BACKGROUND: Health-care providers in the US revealed that a substantial proportion of mNSCLC patients do not receive any first-line therapy and the biggest gaps in care are time inefficiencies in the diagnostic process. The goal of this study was to determine whether such gaps are found in Israel where healthcare is universal and participation in a medical insurance plan is free and compulsory. METHODS: We conducted a retrospective, observational cohort study using the computerized data of Maccabi Healthcare Services, a 2.5 million-member state-mandated health-service. Patients with mNSCLC diagnosed between 2017 and 2018 were followed until December 2019. RESULTS: Among 434 patients (62% male, mean age 68 y, 74% adenocarcinoma), 345 (79%) initiated first-line treatment. Compared to treated, untreated patients (n = 89) were more likely to be older (mean [SD]=71 years [10] vs. 67 [10], p < 0.001), have a higher co-morbidity index (5.6 ([4.4] vs. 4.0 [3.4], p < 0.001), smokers (84% vs. 66%, p = 0.001), and require hospitalization in the year prior to diagnosis (80% vs 61%, p = 0.002). There was no difference in socioeconomic status. Time from first symptom to imaging was longer for untreated than treated patients (6.51 months [4.24, 7.33] vs 3.48 months [2.76, 4.34] respectively, p = 0.22). Predictors of treatment initiation included age< 70 years, non-smokers, EGFR testing performed, ECOG performance status 0-1 and shorter wait from first symptom to imaging. Median time from first symptom to initiation of 1 L, was 7.76 months (6.51-8.75). CONCLUSION: The proportion of untreated mNSCLC patients are comparable to those reported in the US; we did not find health disparities between socioeconomic levels. Our data suggest that the main barrier to effective diagnostic process is the wait between symptom complaint and imaging.

Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential.

Endogenous tissue inhibitors of metalloproteinases (TIMPs) have key roles in regulating physiological and pathological cellular processes. Imitating the inhibitory molecular mechanisms of TIMPs while increasing selectivity has been a challenging but desired approach for antibody-based therapy. TIMPs use hybrid protein-protein interactions to form an energetic bond with the catalytic metal ion, as well as with enzyme surface residues. We used an innovative immunization strategy that exploits aspects of molecular mimicry to produce inhibitory antibodies that show TIMP-like binding mechanisms toward the activated forms of gelatinases (matrix metalloproteinases 2 and 9). Specifically, we immunized mice with a synthetic molecule that mimics the conserved structure of the metalloenzyme catalytic zinc-histidine complex residing within the enzyme active site. This immunization procedure yielded selective function-blocking monoclonal antibodies directed against the catalytic zinc-protein complex and enzyme surface conformational epitopes of endogenous gelatinases. The therapeutic potential of these antibodies has been demonstrated with relevant mouse models of inflammatory bowel disease. Here we propose a general experimental strategy for generating inhibitory antibodies that effectively target the in vivo activity of dysregulated metalloproteinases by mimicking the mechanism employed by TIMPs.

Structural and functional bases for allosteric control of MMP activities: can it pave the path for selective inhibition?

The zinc-dependent matrix metalloproteinases (MMPs) belong to a large family of structurally homologous enzymes. These enzymes are involved in a wide variety of biological processes ranging from physiological cell proliferation and differentiation to pathological states associated with tumor metastasis, inflammation, tissue degeneration, and cell death. Controlling the enzymatic activity of specific individual MMPs by antagonist molecules is highly desirable, first, for studying their individual roles, and second as potential therapeutic agents. However, blocking the enzymatic activity with synthetic small inhibitors appears to be an extremely difficult task. Thus, this is an unmet need presumably due to the high structural homology between MMP catalytic domains. Recent reports have recognized a potential role for exosite or allosteric protein regions, distinct from the extended catalytic pocket, in mediating MMP activation and substrate hydrolysis. This raises the possibility that MMP enzymatic and non-enzymatic activities may be modified via antagonist molecules targeted to such allosteric sites or to alternative enzyme domains. In this review, we discuss the structural and functional bases for potential allosteric control of MMPs and highlight potential alternative enzyme domains as targets for designing highly selective MMP inhibitors.