Conference Scene: Advancing Toward Personalized Medicine

Abstract

Organized by the Cambridge Healthtech Institute, this conference consisted of four major tracks, each of which focused on a topic integral to the development and successful translation of new diagnostic and therapeutic tools and approaches. The theme of these tracks were optimizing clinical trials, implementing personalized medicine, advancing cancer therapy and bridging the silos in biomarker development. Four preconference short courses were also offered that well-complemented these themes, and addressed biomarker assay development/validation, commercial advances in circulating tumor cell assessment, novel cancer biomarkers and biomarker qualification/validation. This conference served as an interactive venue for the networking and exchange of information between researchers, industry, physicians and other attendees on the translation of concepts from the laboratory to the clinic.

The Accelerating Development and Advancing Personalized Therapy (ADAPT) Congress was organized by the Cambridge Healthtech Institute (Needham, MA, USA), which annually produces a number of meetings focused on health-related science and technology. Approximately 450 attendees from a wide variety of backgrounds, including researchers, industry and physicians, participated in this 4-day conference. Four main tracks divided the overall content of the meeting; with each track consisting of two individual, but conceptually related programs, providing participants a total of eight programs to choose from. Talks on ‘Adaptive Clinical Trial Designs’ and ‘Clinical Biomarkers’ comprised Track 1, while Track 2 addressed topics in ‘Personalized Medicine’ and ‘Targeted Therapy‘. ‘Translational Cancer Medicine’ and ‘Circulating Tumor Cells’ were discussed in Track 3, and Biomarker Data Analysis and Protein Biomarkers were the themes of Track 4. Reflecting the diverse backgrounds of the attendees, speakers, likewise, consisted of experts from academia, government, industry and other areas, who together gave over 90 presentations throughout the course of the meeting and preconference short courses [1]. A few of these will be briefly summarized here.

Novel cancer biomarkers

Robert H Getzenberg (Johns Hopkins Hospital, Baltimore MD, USA) chaired this preconference short course, which discussed promising new markers that are potentially useful for cancer detection, disease monitoring and selection of therapy. He was the first speaker, and presented data from studies performed to identify and evaluate the colon cancer-specific antigens -2 and -4. Recognizing that visibly altered nuclear structure is a common feature of malignant cells, a proteomics-based approach was utilized to identify proteins associated with these alterations, ultimately allowing the discovery of these antigens. The data indicated that circulating concentrations of these biomarkers can be used to differentiate patients with colon cancer from those who are healthy or have other conditions, and therefore, may be useful as serum-based assays to aid in colorectal cancer detection.

Baolin Zhang (US FDA, Bethesda, MD, USA) spoke on predicting tumor resistance to death receptor-targeted therapies. Emphasizing the significant role that drug resistance can play in treatment failures, Zhang highlighted several of the key benefits provided by predictive biomarkers. These included the ability to differentiate patients likely to benefit from a particular treatment from those that are not, the ability to better optimize treatment schedules and dosing, and an improved efficiency of developing new anticancer treatments. Also emphasized during this talk was the fact that because the molecular targets of some treatment agents are associated with defective survival or proliferation pathway signaling, assessing the status of these targets in tumor tissue, in addition to an indepth knowledge of the therapeutic agent's mechanism of action and potential pathways to escape this mechanism, are all useful information for selecting predictive markers. In his discussion of death receptors (DR) as the therapeutic target, Zhang presented data showing that DR4/DR5 surface receptors are lacking in cells naturally resistant to TRAIL-induced apoptosis, and that this deficiency is sufficient to result in resistance against TRAIL-dependent anticancer agents. Consequently, he pointed out that knowing a patient's tumor is deficient might be useful in therapy selection. Similarly, data were presented suggesting that initially sensitive tumors can gain resistance after contact with low drug concentrations over time, and indicated that this was associated with decreased surface DR4/DR5 expression. Importantly, the talk emphasized the need to perform validation studies of potential new biomarkers in appropriately designed clinical trials and to use standardized methodologies to measure them.

Shannon R Payne (Epigenomics, Inc., Seattle, WA, USA) spoke about the use of the DNA methylation biomarker septin 9 as a blood-based test to aide in the detection of colorectal cancers. Payne discussed the fact that despite colorectal cancers being a major cause of cancer-related mortality in the USA, and evidence suggesting that early detection is associated with a decrease in mortality, only approximately 50% of those eligible under the American Cancer Society guidelines are currently being screened. It is believed that, a minimally invasive blood-based test may improve compliance with screening. Payne described septin 9, which belongs to the septin family (a conserved family of GTP-binding proteins) and the development of the SEPT9 real-time qPCR assay. Development of this test was made possible by the understanding that DNA methylation patterns can be changed in tumors, and that cell-free DNA is shed by malignant cells into diverse body fluids, making DNA methlytion markers potentially useful for cancer screening. A prospective, multi-institutional study (PRECEPT) is currently being conducted to validate this marker for the early detection of colorectal cancer.

Circulating tumor cells

Harold Garner (Xanapth, Dallas, TX, USA) discussed multiplexed profiling of circulating tumor cells (CTCs) using a hyperspectral imaging system. It is generally recognized that profiling CTCs can reveal detailed information that is valuable for optimizing and better individualization of cancer treatment. Garner highlighted the inherent difficulties with harvesting adequate amounts of marker information from a relatively small number of cells. The use of a hyperspectral microscopy imaging system was developed, which can quantify protein expression levels of multiple markers in individual intact cells simultaneously. A number of markers, such as cytokeratin, HER-2, estrogen receptor and progesterone receptor, are currently available in established panels.

Katarína Kološtová (Charles University, Prague, Czech Republic) spoke about a project involving gene-expression profiling of CTCs in breast cancer patients. As discussed in several presentations throughout the conference, the molecular interrogation of these cells as a potential tool for personalizing treatment regimens was again very appropriately emphasized. The need to obtain more information about CTCs in general, such as their source (primary site vs bone marrow), influence of microenvironment on establishment of metastatic deposits and patient-specific differences, Kološtová pointed out, requires investigation at the single-cell level. It was also noted that evidence suggests disseminated tumor cells identified in bone marrow and CTCs most likely provide independent prognostic information, with disseminated tumor cells probably representing a more static process as compared with CTCs that may reflect tumor proliferation.

Farideh Z Bischoff (Biocept, San Diego, CA, USA) described the assay optimization studies performed on a microfluidic device (Cell Enrichment and Extraction [CEE™]) for enumerating and molecular analysis of CTCs. This system utilizes a silicone channel combined with immunocapture of epithelial cells using an antibody cocktail. Studies using blood spiked with SKBR3 cells demonstrated very high recovery, and the percentage of cells captured was independent of the number introduced into the system. Benefits of this system were discussed, including no need to manipulate captured cells, the ability to perform microscopic examination of the channels immediately at low or high magnification by either brightfield or fluoresceny microscopy, and the ability to conduct sequential assays on the same channel. This methodology is also compatible with additional studies using immunocytochemistry, FISH or PCR techniques.

Beverly C Handy (The University of Texas MD Anderson Cancer Center, Houston, TX, USA) discussed current literature supporting the clinical utility of enumerating CTCs. Multiple studies confirm that baseline CTC measurements can provide independent prognostic information in patients with a variety of epithelial tumor types. In addition, data suggest that serial determinations may also be useful for monitoring patients undergoing treatment. More well-designed studies examining the role of CTC analysis are needed to examine its utility in additional tumor types, to compare the information it provides to imaging studies (can it be an earlier indicator of disease status), to examine its potential utility as a surrogate end point in clinical trials and better understand the significance of differences in expression profiles between primary tumors and CTCs.

Conclusion

This meeting was extremely informative, and well-organized. With a large number of presentations offered, comprehensive coverage of the topics delineated in each of the four tracks was provided. Sufficient time was always allotted after each talk for questions. Recognition of the need to conduct well-structured prospective studies to validate new emerging markers was a common theme, emphasized by many presenters throughout the meeting. Standardization of methodologies to measure these markers will also become more paramount as they are translated from the research laboratory to the clinic. Nonetheless, it is recognized that the identification and availability of appropriate biomarkers are key to making personalized medicine and optimization of treatment a reality.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.