Early therapy assessment of combined anti-DR5 antibody and carboplatin in triple-negative breast cancer xenografts in mice using diffusion-weighted imaging and (1)H MR spectroscopy

TUMOR NECROSIS FACTOR-related apoptosis-inducing ligand (TRAIL) binds several receptors including DR4, DR5, DcR1, DcR2, and osteoprotegerin (1-8), and has presented a high anti-tumor effect in both in vitro (3,5) and in vivo studies (9,10) of several cancer types. However, a concern was raised in its clinical translation due to severe hepatotoxicity revealed during preclinical studies (11), potentially related to its binding to the multiple receptors (1-8). Therefore, a monomeric monoclonal antibody named TRA-8 targeting only DR5 was developed, and provided excellent preclinical efficacy in various cancers without hepatotoxicity (12). Oliver et al recently demonstrated the significant anti-tumor effect of TRA-8 alone or in combination with abraxane (or doxorubicin) in murine models of triple negative (ER/PR/Her2 negative) breast cancer (TNBC) (13), consistent with Rahman et al findings regarding the efficacy of TRAIL for TNBC cell lines (14). TNBC have a higher pathologic complete response (pCR) to chemotherapy (15) and good prognosis (16). However, a higher likelihood of relapse was also observed, when a pCR was not achieved (9,10,16). Therefore, it would be advantageous to achieve a pCR for TNBC with an advanced biological therapeutic agent like TRA-8. The therapeutic efficacy of TRA-8 could be further improved when combined with carboplatin. Carboplatin, a platinum-based chemotherapeutic agent, induces cell death by means of blocking DNA replication and has been used to treat various cancerous diseases (17). Of interest, TNBC cells have many similar characteristics with BRCA1-mutated cells (18,19) having significant in vitro sensitivity to carboplatin (20). Chang et al reported that the dual combination chemotherapy with docetaxel and carboplatin achieved 26.8% of pCR rate among TNBC patients (21). Furthermore, the improved therapeutic efficacy of TRA-8 combined with carboplatin was validated in ovarian cancer murine models (22). While the combined use of TRA-8 and carboplatin could be superior to monotherapy, it might induce a range of therapeutic responses among TNBC patients. It would be beneficial to assess early tumor response to therapy for each individual patient to tailor the therapeutic strategy. Diffusion-weighted imaging (DWI) has been used to measure the increased water mobility due to cell death in response to effective therapy, before noticeable change in size or morphology of breast cancer (23-26). Water diffusion is represented with ADC (apparent diffusion coefficient) value. 1H magnetic resonance spectroscopy (MRS) has been also used to measure early therapeutic response by quantifying lipid concentration; lipid has been observed to increase in apoptotic cells, presumably due to the inhibition of phosphatidylcholine biosynthesis and the activation of phospholipases (27), and fat–water ratio (FWR) has been validated as a surrogate biomarker to evaluate chemotherapy for breast cancer (28,29). We hypothesized that DWI and MRS would be able to detect the early response of TNBC following the dual combination therapy with TRA-8 and carboplatin. Two TNBC murine models were used to test this hypothesis. The therapeutic efficacy was assessed by means of monitoring tumor volume and analyzing histologic samples, and correlated with the early changes of ADC and FWR in the tumor region.