(ChemotherapyAdvisor) – An extensive genomics study of women with the high-grade serous cancer (HGSC) subtype of ovarian cancer has identified LRP1B, a member of the lipid transporter family, as a “potential contributor to the emergence of chemotherapy resistance,” investigators reported in the August 15 issue of Cancer Research.
David Bowtell, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues used high-resolution single-nucleotide polymorphism arrays to examine spatial and temporal genomic variation in HGSC. Multiple metastatic lesions from individual patients were analyzed, as were 22 paired pretreatment and posttreatment samples.
“In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy,” they reported.“Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin.”
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Dr. Bowtell said in a press release, “We were surprised by the extent of variation that was present among the tumor deposits collected at surgery, and by how far the tumors could evolve during therapy. The existence of multiple cancer genomes in an individual patient could provide many opportunities for the cancer to circumvent chemotherapy and may help explain why it has been so difficult to make progress with this disease. If we can comprehensively map the mechanisms that confer resistance, we may be able to predict whether some women are likely to respond to a certain drug or not, and find ways of reversing resistance.”
The study, part of the International Cancer Genome Consortium, underscores the international collaboration needed to map emergence of chemotherapy resistance in ovarian cancer and other solid cancers systematically, since it is difficult to obtain paired pre- and post-treatment samples. Dr. Bowtell said he believes collection of biopsy tissue in the relapse setting will increasingly be seen as essential for predicting response in the clinic and understanding why treatment failure occurs.
