Using extracellular biomarkers for monitoring efficacy of therapeutics in cancer patients: an update

Abstract

Rapidly detectable and easily accessible markers of tumor cell death are needed for evaluating early therapeutic efficacy for immunotherapy and chemotherapy so that patients and their physicians can decide whether to remain with a given therapeutic strategy. Currently, image-based tests such as computed tomography scans and magnetic resonance imaging are used to visualize the response of a patient's tumor, but often these evaluations are not conducted for weeks to months after treatment begins. While serum levels of secreted proteins such as carcinoembryonic antigen and prostate specific antigen are commonly monitored to gauge tumor status during therapy and between image evaluations, the levels of these proteins do not always correlate well with the actual tumor response. In laboratory studies, it has been shown that tumor cells undergoing apoptosis can release cellular components into cell culture media such as cytochrome c, nucleosomes, cleaved cytokeratin-18 and E-cadherin. Studies of patient sera have found that these and other macromolecules can be found in circulation during cancer therapy, providing a potential source of material for monitoring treatment efficacy. In the future, analysis of biofluids from severe combined immunodeficiency mice bearing patient tumor specimens treated with a targeted therapy such as Apo2L/tumor necrosis factor-related apoptosis-inducing ligand will be useful in the preclinical identification of therapy response markers. In this review, the current status of the identification of serum markers of tumor cell apoptosis is provided, as well as a discussion of critical research questions that must be addressed and the considerations necessary when identifying a marker that reflects true clinical outcome.

Fig. 1

Strategy for monitoring tumor response in the clinic. After detection, a first-line cancer therapy is chosen and traditionally, follow-up is conducted months later with imaging techniques such as X-ray, computed tomography (CT) scan or magnetic resonance imaging (MRI). This time delay could result in the progression if the tumor is not sensitive to the initial therapy. With therapeutic efficacy or response markers, blood could be sampled from patients within hours to days following the administration of treatment. These biomarkers may have several origins: 1 mitochondria, 2 nucleus, 3 cytosol or 4 membrane (see the text and table for details). At this time the absence or presence of biomarkers could guide the course of therapy by providing more information about the immediate response of the tumor. When response markers are not detected, the therapy would be adjusted to another available, alternative therapeutic agent. Once again, blood would be sampled and the presence of biomarkers assessed

Fig. 2

E-cadherin is released from Colo 205 cells as they undergo Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Cells were treated with 250 ng/ml Apo2L/TRAIL for 2, 4, 8, and 16 h. Cell culture media was collected and E-cadherin was immunoprecipitated from the samples and then detected on a western blot with the HECD-1 clone. C control, T Apo2L/TRAIL-treated

Fig. 3

Scheme for validating response markers as measures of true clinical outcome. Initially, the study of human tumor specimens engrafted into immunocompromised mice will be most useful for the identification of candidate markers of tumor response when treated with a targeted therapy (e.g. Apo2L/TRAIL, Herceptin^®). Once identified and confirmed with proteomic and/or metabonomic studies, other more non-specific therapies can be investigated (e.g. chemotherapy, radiation). Inquiries into whether the biomarkers are tumor or treatment specific will be elucidated. Once established, clinical studies will identified whether the same molecules are detectable in patients during therapy. Importantly, cohorts of patients will need to be followed for assessment of tumor response with traditional techniques such as tumor imaging and histology and these evaluations will need to be correlated with the newly identified therapeutic efficacy markers to assess their measurement of true clinical response