Virtual Library

Start Your Search

David Mark Jablons



Author of

  • +

    MS31 - Clinical Science in Mesothelioma (ID 809)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 205 AC
    • +

      MS31.03 - Targeting the Hippo Pathway (Now Available) (ID 11537)

      14:00 - 14:15  |  Presenting Author(s): David Mark Jablons

      • Abstract
      • Presentation
      • Slides

      Abstract

      The prognosis for malignant pleural mesothelioma (MPM) remains poor and many anticipated advances in MPM treatment have been disappointing. One reason for the failure of conventional cytotoxic drugs is that they do not address the cancer stem cell population or the stem cell pathways that drive tumor resistance and resurgence following treatment. Cancer stem cells are defined by their properties of self-renewal, pluripotency, a high proliferative capacity and the ability to resist standard chemotherapy and radiation. Among the stem cell pathways, Hippo has proven to be critical to driving growth in MPM with mutations along this pathway implicated in the majority of MPM tumors.

      The Hippo pathway is a highly conserved regulator of organ size by regulating contact inhibition and of stem cell proliferation and maintenance.(1) The largest and most comprehensive genomic analysis to date of transcriptomes, whole exomes and targeted exomes from 216 MPM samples found Hippo pathway signaling to be the number one most significantly mutated pathway in mesothelioma with a Q-value of 1.70E-17, driven by mutations, copy number variations and fusions in NF2, LATS1, LATS2 and MST1.(2) One of the most frequently mutated genes in MPM is Neurofibromatosis type 2 (NF2) tumor suppressor, located at chromosome 22q12, and is detected in 40% to 50% of MPM tumors.(3) Large tumor suppressor homolog 2 (LAST2) gene, which is located at chromosome 13q12, is another frequently inactivated gene that is detected in 13% of MPM tumors. (3, 4) Inactivation of NF2 and LATS2 by deletion and/or mutation often contribute to dysregulation of Hippo pathway.(5) In addition to LATS2, its closest gene family member LATS1 another Hippo pathway gene, has also recently been identified to be dysregulated in MPM, though less commonly than LATS2. LATS1 is located on chromosome 6 and changes in copy number variation and fusions to Presenilin 1 (PSEN1) on chromosome 14 have been observed in MPM.(2, 3) Mammalian sterile-20 like kinase 1 (MST1) is an important upstream kinase in the Hippo pathway that has also been found to be dysregulated in MPM.(2) Given the high frequency of mutations and dysregulation in the Hippo pathway, it is a promising potential area of drug development.

      One specific target along the Hippo pathway is blocking Yes-associated protein (YAP) activity. In normal cells, Merlin, a protein encoded by NF2, and LATS2 contribute to the phosphorylation of the transcription factor YAP at S127,(6) resulting in YAP ubiquitination and activation of Hippo pathway to control cell proliferation. In MPM tumor cells, inactivation of NF2 and LATS2 prevent the phosphorylation of YAP at S127, which results in YAP relocation from the cytosol to nucleus where it interacts with TEA domain transcription factors (TEAD). In addition, constitutively activation of YAP has been identified in over 70% of primary MPM tumors, (3, 5, 7) and YAP activation leads to Hippo signaling attenuation and transcription of downstream target genes, such as connective tissue growth factor (CTGF) and Cyr61.(8) Low Merlin expression (NF2), results in YAP1 activation, and has been shown to be associated with worse clinical outcomes with shorter times to recurrence and shorter overall survival times in patients with MPM.(9) Blocking YAP activity, either via upstream inhibition of one of the several pathways that regulate YAP and Hippo or via direct YAP/TEAD inhibition is an area of active interest.(10) Several novel small molecule YAP inhibitors are in preclinical development with promising results and may enter clinical trials in the near future.

      FIGURE: Hippo Pathway Potential Drug Targets

      figure.jpg

      References

      1. Ramos A, Camargo FD. The Hippo signaling pathway and stem cell biology. Trends in cell biology. 2012;22(7):339-46.

      2. Bueno R, Stawiski EW, Goldstein LD, Durinck S, De Rienzo A, Modrusan Z, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nature genetics. 2016;48(4):407-16.

      3. Miyanaga A, Masuda M, Tsuta K, Kawasaki K, Nakamura Y, Sakuma T, et al. Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2015;10(5):844-51.

      4. Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer research. 2011;71(3):873-83.

      5. Felley-Bosco E, Stahel R. Hippo/YAP pathway for targeted therapy. Translational lung cancer research. 2014;3(2):75-83.

      6. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes & development. 2007;21(21):2747-61.

      7. Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X. Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer science. 2010;101(5):1279-85.

      8. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nature reviews Cancer. 2013;13(4):246-57.

      9. Meerang M, Berard K, Friess M, Bitanihirwe BK, Soltermann A, Vrugt B, et al. Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma. Molecular oncology. 2016;10(8):1255-65.

      10. Woodard GA, Yang YL, You L, Jablons DM. Drug development against the hippo pathway in mesothelioma. Transl Lung Cancer Res. 2017 Jun;6(3):335-342.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P2.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 965)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
    • +

      P2.16-12 - Expanded Data Confirm Molecular Testing Identifies Lung Adenocarcinoma Patients, Including Stage IA, Who Benefit from Adjuvant Chemotherapy (ID 14532)

      16:45 - 18:00  |  Author(s): David Mark Jablons

      • Abstract
      • Slides

      Background

      A clinically certified, 14-gene quantitative PCR expression assay has been validated to assess mortality risk in early-stage lung adenocarcinoma. Molecular stratification may identify those stage I-IIA patients who are in most need of potentially life-saving intervention after resection, including stage IA patients for whom chemotherapy is never recommended.

      Method

      Prospective molecular risk-stratification by the 14-gene assay was performed on 200 consecutive patients with stage I-IIA lung adenocarcinoma after complete surgical resection at a single institution. Adjuvant chemotherapy was recommended for molecular high-risk patients. Kaplan-Meier analysis and log-rank tests were used to evaluate differences in disease free survival.

      Result

      Average age of patients was 68 +/- 10 years, 62% were female and mean follow up was 24 months. The recurrence rate among all patients was 9%. However, 87 patients (44%) were found to be molecular high-risk and had a recurrence rate of 17%, whereas the 113 patients (56%) who were molecular low-risk had a recurrence rate of only 3% (p<0.0001). Even among the stage IA patients, 41 (33%) were found to be molecular high-risk. The recurrence rate in molecular low-risk stage IA patients was only 1%, compared to 15% in stage IA patients who were identified as molecular high-risk (log-rank p=0.003). Of the 41 stage IA patients found to be molecular high-risk, 24% agreed to undergo adjuvant chemotherapy; there have been no recurrences among these treated high-risk patients. In contrast, the KM estimate of 5-year disease free survival among stage IA high-risk patients who did not receive adjuvant chemotherapy was 51% (log-rank p=0.005). pervenio stage ia figure.jpg

      Conclusion

      This prospective, single-institution study further demonstrates the clinical utility of the 14-gene molecular prognostic assay in the management of early stage lung adenocarcinoma. Adjuvant chemotherapy guided by molecular prognosis in the earliest stages of disease, including stage IA, may prevent a significant number of recurrences and deaths.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P3.03 - Biology (Not CME Accredited Session) (ID 969)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
    • +

      P3.03-24 - Incorporation of a Molecular Prognostic Classifier Improves Conventional Non-Small Cell Lung Cancer Staging (Now Available) (ID 14531)

      12:00 - 13:30  |  Author(s): David Mark Jablons

      • Abstract
      • Slides

      Background
      Despite significant advancements in the understanding of the molecular genetics of tumor biology, the 8th Edition of Non-Small Cell Lung Cancer (NSCLC) staging adopted in 2018 remains dependent upon tumor size, nodal spread, and metastasis. The survival of patients with early stage NSCLC remains poor and further improvement in staging is needed to better inform adjuvant therapy. In this study, we explored the integration of a clinically validated, molecular prognostic classifier into conventional staging.
      Method
      A novel staging system, TNMB (“B” indicating Biology), that integrates a 14-gene molecular prognostic classifier with the 8th Edition, was developed using 332 patients with non-squamous NSCLC resected at the University of California, San Francisco (UCSF). TNMB was subsequently validated on a separate multi-institutional international cohort of 1,373 patients. Reclassification metrics were evaluated from adoption of TNMB and the 8th Edition. Result
      Adoption of TNMB improved prognostication of overall survival significantly more than adoption of the 8th Edition. TNMB resulted in Net Reclassification Improvement of 0.33 (95% CI 0.24-0.41), relative Integrated Discrimination Improvement of 22.1% (95% CI 8.8-35.3%), and Reclassification Calibration Statistic from 36 to 18 (P-Value 0.03 to 0.73). In contrast, the 8th Edition resulted in no change in Net Reclassification Improvement 0.03 (95% CI -0.00-0.06) or relative Integrated Discrimination Improvement -2.5% (95% CI -17.6-12.4%) and resulted in Reclassification Calibration Statistic from 134 to 22 (P-Value <0.01 to 0.27). Conclusion
      Incorporation of a molecular prognostic classifier offers substantial improvement to conventional staging of NSCLC and may lead to a significant impact on clinical decision-making in early stage disease where identification of high risk patients is needed to guide adjuvant therapy. Our findings may encourage application of molecular prognostic classifiers into the refinement of conventional staging for other solid tumors.

      Overall Survival of Non-Small Cell Lung Cancer Patients Following Surgical Resection by 7th Edition, 8th Edition, and TNMB Staging. TNMB had distinct separation of survival by stage and larger range of survival between early and late stages compared to conventional staging.

      14531.png



      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    WS02 - Mesothelioma Workshop (ID 996)

    • Event: WCLC 2018
    • Type: Workshop
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 08:00 - 11:15, Room 205 AC
    • +

      WS02.13 - Session 3: Transcriptome Changes and Mutations in Mesothelioma - Somatic, Germline, BAP1 and more (Now Available) (ID 14757)

      10:10 - 10:10  |  Presenting Author(s): David Mark Jablons

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.