In collaboration with the Lastwika and Houghton labs, the Lampe laboratory performs studies to find blood tests or protein biomarkers that can indicate if and where a person has cancer and if it is present, how to best treat it. Specifically, we are working to find early detection, recurrence or response biomarkers of colon, breast, and lung cancer. Useful biomarkers can allow doctors to find and treat cancer earlier and better saving lives, reducing costs and allowing for “personalized or precision medicine” where the treatment is specific for each person’s disease. Although in the past we have used a variety of mass spectrometry methods, currently our primary approach is to utilize high density antibody arrays to determine proteomic, glycoproteomic and autoantibody markers of disease. We are especially interested in markers where the level of a protein, the level of its glycosylation or whether autoantibodies are produced to it can yield multi-dimensional information on each protein. We consider specific proteins that show consistent cancer-specific changes in 2 or 3 of these measurements to be “hybrid markers”. We hypothesize these markers will suffer less variation between different individuals since one component can act to “standardize” the other measurement.

Our approach to biomarker discovery is unique in several ways. Our discovery arrays contain over 3000 antibodies printed in triplicate giving us reliable and highly consistent data. The fact that we assay proteomic, glycomic and autoantibody changes gives us broad coverage of potential biomarkers. We can screen hundreds of samples in a week reducing false positives. For early detection, we have utilized large pre-diagnostic sample sets from screening cohorts (WHI, CHS, PLCO, NLST) reducing the chance that potential early detection biomarkers are not simply related to inflammation or disease burden. We validate in similar sized sample sets and the high density of the arrays allow us to retain hundreds of candidate biomarkers. Thus, we do not spend the time to develop individual assays until biomarkers have passed multiple validation steps and their utility is more clear reducing costs and prioritizing effort.

Lung cancer screening (LCS) trials using low dose computed tomography (CT) can reduce mortality in individuals with high-risk smoking histories. However, there are critical limitations to current LCS approaches, which rely solely on interpretation of imaging findings, including: a) The mortality benefit is largely driven by patients with adenocarcinoma (AD) lung cancer, with limited benefit for squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). b) CT screening frequently results in “indeterminate nodules” for which clinical management to determine malignancy are based on AD trajectories that are largely limited to repeat imaging. c) Adherence to imaging follow-up is necessary to achieve AD mortality benefits, but follow-up imaging rates are clearly suboptimal.  d) Current LCS protocols and resulting guidelines were created based on evidence from trial cohorts that do not reflect the racial and socioeconomic diversity within the at-risk population. The recent United States Preventive Services Task Force recommendations for LCS state, “Research to identify biomarkers that can accurately identify persons at high risk is needed to improve detection and minimize false-positive results.” Our biomarker data show lung cancer histological subtypes display distinct risk factors consistent with their different pathology, etiology and outcomes. We are currently employing a novel lung subtype-specific approach to address the shortcomings of current LCS. Our methods include both detection of specific blood autoantibody levels and quantitative imaging features via a collaboration with Paul Kinahan’s group at UW Radiology to assess the distinct risk of AD, SCC and SCLC lung cancer. This approach will overcome critical limitations of current guidelines to increase SCLC and SCC detection sensitivity and better classify AD indeterminate nodules to identify patients which benefit from immediate action. This project is currently funded by the NCI/NIH Lung SPORE (Specialized Program of Research Excellence) awarded to the Fred Hutch and UW.

Small-cell lung cancer (SCLC) kills over 30,000 Americans every year and has a dismal 5-year overall survival rate of less than 7%. However, SCLC outcomes are greatly improved by early detection and intervention, with a nearly 50% 5-year survival rate for patients diagnosed at an early stage. These discrepant outcomes indicate that, by far, the majority of SCLC cases are diagnosed at later stages at which tumors rapidly become resistant to therapy, with death quickly following. Thus, an effective early detection strategy is necessary that both identifies cancer in people at high risk and facilitates non-invasive imaging that can confirm and delineate small tumors to guide surgical resection and treatment. We have found that autoantibodies are present in the plasma of essentially all SCLC patients (much more common than in other major cancers) and have validated at least 7 autoantibody-identified neoantigens expressed by SCLC tumors that can be exploited as highly cancer-specific early detection biomarkers and/or imaging targets. We envision an early detection/diagnosis platform performed during the recommended annual low-dose computed tomography (LD-CT) lung cancer screenings for heavy smokers. However, LD-CT and all current imaging modalities are not suitable for SCLC early detection even in smoking enriched populations due to lower than required sensitivity/specificity and risk/benefit analyses.  We envision a two-tiered approach, with a blood test that detects the presence of autoantibodies specific for SCLC that would trigger immuno-positron emission tomography (immunoPET) imaging via a radioimmunoconjugate that specifically targets the autoantigenic proteins expressed only on SCLC tumors. The blood test ensures that only high-risk individuals are screened and the immunoPET confirms and localizes the tumor for future treatment. This work is funded by an R01 from NCI/NIH as part of the Consortium for imaging and Biomarkers.

We and others have shown that post translational modifications can cause the creation of disease specific autoantibodies.  Seven of the autoantibodies that we found in SCLC patients are to integral membrane proteins that might make suitable targets for immune based therapies.  By sequencing the IgG variable regions from patient B cells, we can make recombinant human IgG that could be used as antibody drug conjugates or we can make chimeric antigen receptor T (CAR T) cells to direct and specifically attack the tumor. The latter approach is a collaboration with Dr. Kristin Lastwika’s lab and has been funded by an NCI/NIH U01 as part of the Small Cell Lung Cancer Consortium with her as contact PI.

We are funded by NCI to find early detection biomarkers for non-small cell and small cell lung cancer (NCI, U01, R01, P50 grants). We are also validating early detection biomarkers of colon and breast cancer via a Clinical Validation Center grant from the Early Detection Research Network  (EDRN) funded by the National Cancer Institute (NCI, U01 grant).

Finally, we continue our long-term interest in the cell biology and signaling associated with gap junctions.

Learn more about our gap junction research