Dr. Paul Bunn

       在今天下午的全體大會的主題演講環節，首位登場的專家是來自美國的Paul A. Bunn教授，他的報告是Precise Cancer Medicine and Genomic Testing 。以下是Paul A. Bunn教授報告的精彩預告以及本報記者的采訪，先睹為快!

        Paul A. Bunn,Distinguished Professor and James Dudley Chair of Lung Cancer Research, Univ. of Colorado, Aurora, Colorado, USA

        The long term goal of cancer therapy is to provide the right treatment to the right patient at the right time.

        Recent research showed that many lung cancers are caused by specific molecular alterations that drive the cancer growth and are present in all cancer cells. These specific molecular alterations could be identified from patient biopsies. Pharmaceutical companies developed oral pills that were specific for these molecular alterations and which produced high response rates with low toxicity rates in the patients identified to have these genetic changes. Many such genetic changes have now been identified and many new drugs have been approved that are specific for the abnormality. New next generation tests can identify all of the genetic changes for which drugs are available. New research is developing tests on circulating DNA from the blood.

        The first molecular change identified in lung cancer was mutations in the EGFR gene. Gefitinib and erlotinib were shown to produce very high response rates and long survival in mutant patients. Subsequently, it was discovered that resistance developed in all patients. In most cases, the resistance was caused by a second mutation in the targeted gene. For EGFR mutations, this new "gatekeeper" resistance mutation was in a portion of the gene called T790M. In most other instances, resistance was due to activation of alternative signaling pathways.

        Several third generation EGFR TKIs were developed to bind to cells with the EGFR T790M mutation. And these have proven to be very safe and effective. Other driver alterations for which drugs are approved or are in development include the ALK, ROS, RET, HER2, NTRK, MET, FGFR and other genes. Unfortunately, while the new pills are very effective, resistance is inevitable. Future research must identify drug combinations that will lead to more complete response, longer remissions and even cure of patients.

        In addition to the development of effective molecular therapies, the field of immunotherapies is emerging. Biomarkers to determine which patients are most likely to benefit are under development. High expression of a protein called PD-L1 can predict patients most likely to benefit from these agents. Unfortunately, assessment of PD-L1 expression is not very effective in determining which patients will not benefit. After failure of chemotherapy these immunotherapies are better than subsequent chemotherapy and for patients with high PD-L1 expression, these agents are being compared to chemotherapy in the first line.

        Thus, the development of molecular therapies and immunotherapies has proved to be a step toward being able to provide the best treatment to the best patient, but until we cure patients we will rely on future research to reach our goals.

       ■Dialogue

        Dr. Paul A. Bunn is a renowned oncologist, especially focusing on novel therapies for lung cancer. In an interview with CMT(China Medical Tribune), Dr.Bunn shared his view of future directions of lung cancer research.

        While I strongly believe that research in early detection and prevention is critical to decrease lung cancer death rates, basic research advances have revolutionized the opportunities to improve lung cancer therapies in two major areas.

        The first area is molecular targeted therapies.Majority of lung cancers arise due to driver genetic alterations, which may be mutations, translocation, fusions or increases in gene copy number but always activate a single driver oncogene which is usually a growth factor receptor. These alterations in the growth factor receptor can be targeted by oral medicines called TKI. There are more and more of these genetic changes being identified so that current research is focusing on the ability to assess multiple abnormalities rapidly and at the same time on small amounts of tissue. Research is also examining whether these genetic analyses can be done from blood samples rather than a biopsy. Future research will identify the causes of resistance so that effective therapies at relapse can be developed and so that rational combinations can be developed.

        The second area is immunotherapies.For cancers to grow, they must avoid killing by the immune system. One way is by making proteins such as PD1 protein (checkpoint inhibitors) that block lymphocytes from killing them. Investigators have developed monoclonal antibodies to block these checkpoint inhibitors. Future research will develop markers to determine which patients will derive the most benefit, and will also combine various immune therapies to obtain more frequent and lasting remissions and perhaps cure some of the patients.

        In this interview,Dr.Bunn also gave his interpretation of "Precision Medicine"."Precision Medicine refers to the ability to identify the right treatment for the right patient at the right time. Other terms identifying the same goal are personalized therapy or targeted therapy.

        The major impetus for this field emerged when molecular targets were identified on tumor cells that were not present in normal cells.

        These molecular targets are genetic mutations, translocations, and fusions that activate specific oncogenes. If a patient has such a molecular abnormality, then relatively non-toxic pills are likely (about 90%) to produce symptom and survival benefit such patients. Molecular tests can also identify the cause of resistance in many patients when these pills no longer work so that another oral agent can be used. Lung cancer patients have especially high rates of having one or more of these molecular targets but they are now being identified in many types of cancer. We would like to be able to identify which patients would also benefit most from specific chemotherapies and immunotherapies. However, developing biomarkers to identify the patients most likely to benefit from these therapies lags behind the development of molecular biomarkers."(Interviewed by JingHong Xu from CMT)