The American Association for Cancer Research is an annual showcase of the latest scientific cancer research, with updates on phase I, often first-in-human clinical trials.
The oral therapy cabozantinib has been shown to stabilize and even resolve metastatic bone lesions in patients with metastatic castration-resistant prostate cancer (mCRPC).1Although the study was initially set to randomize all patients to either oral cabozantinib or placebo, the randomization was stopped after an interim analysis showed cabozantinib was able to effectively shrink bone lesions. Of the 154 patients who could be evaluated, 72% had regression of their soft tissue lesions and 68% had improvements in bone lesions, including 12% who had complete resolution.
At AACR, a poster presentation by researchers from the Institute of Cancer Research in London, England, revealed some of the ways in which cabozantinib is able to target prostate cancer bone lesions.2The researchers used a mouse model of prostate cancer that produces measurable bone metastases. By injecting the mouse model with prostate cancer cells labeled with a bioluminescent marker, researchers were able to track the cancer cells as they destroyed normal bone tissue and developed into bone lesions in the mouselesions with the same features as bone tumors that occur in human patients.
When these bone metastases-positive mice were treated with cabozantinib, the animals showed evidence of inhibition of tumor growth and tumor cell death, similar to what has been seen in clinical trials. Radiological scans of the bones of the mice showed a fair amount of normal bone tissue returning compared to mice were treated with a placebo.
Cabozantinib (Cometriq), an inhibitor of multiple tyrosine kinases including RET, MET, and VEGFR2, is being investigated as a treatment for advanced prostate cancer in two phase III trials and is already approved by the FDA for treatment of progressive metastatic medullary thyroid cancer.Eribulin mesylate (Halaven) is approved for advanced metastatic breast cancer and is undergoing clinical testing for other cancers, including phase III trials in soft-tissue sarcoma and lung cancer. Eribulin is a synthetic version of a molecule derived from a marine sponge that is able to arrest cell division by inhibiting cells’ ability to polymerize the protein tubulin, an essential component for cell replication. Although treatment with eribulin can cause tumor regression via its cell cycle arrest function, exactly how the drug works is still not clear.
Several presentations at AACR investigated potential mechanisms for the antigrowth effects of eribulin. The combined results suggest eribulin may have antimetastatic effects.
Researchers demonstrated evidence supporting a previous observation that eribulin can disrupt vascular activity.3Using a rat model of human breast xenograft tumors, researchers from Eisai Co., which manufactures eribulin, found that the drug can improve blood perfusion within the core of these xenograft tumors, preventing hypoxic conditions. This supports the role of eribulin in inhibiting hypoxia, and therefore potentially inhibiting metastasis of tumor cells, a process that has been shown to occur under hypoxic conditions. The results also support the role of eribulin in remodeling vasculature morphology.
Another study, also presented at AACR, demonstrated that eribulin is able to change the expression level of genes that may function in the epithelial- mesenchymal transition (EMT).4The EMT is the process by which tumor cells acquire several characteristics, such as the ability to migrate, that are common to mesenchymal cells. This transition is thought to facilitate the process of tumor metastasis. The study measured the expression level changes of sets of genes among breast cancer cell lines treated with either eribulin or paclitaxel, a cytotoxic chemotherapy agent also known to target tubulin and cause cell-cycle arrest. Genes associated with the EMT were upregulated in breast cancer cell lines that had resistance to eribulin. The study also identified active pathways in breast cancer lines that were particularly sensitive to eribulin. Overall, the results showed that gene expression may be used to predict the sensitivity of breast cancer to eribulin, but additional studies are needed.Ibrutinib, a selective inhibitor of Bruton’s tyrosine kinase (Btk) is currently in phase II development for hematologic malignancies, including non- Hodgkin lymphoma and mantle cell lymphoma (MCL). In a presentation at AACR, researchers demonstrated that the drug is able to inhibit the adhesion and migration of malignant MCL cells using a mouse cell model, although more studies on this mechanism are needed.5
In clinical trials, patients treated with ibrutinib had an observed increase of MCL cells in the circulating blood that was followed by a reduction in tumor burden, suggesting that malignant cells were traveling from the tumor to the peripheral blood. The results presented at AACR showed that mice treated with ibrutinib had lower levels of malignant cells that traveled to and grew in lymph nodes and in the bone marrow.