Spotlight on Novel Agents in Early Development

Tyrosine Kinase Inhibitor Targets Bone Metastasis

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 mouse—lesions 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.

Mechanisms for the Antineoplastic Effects of Eribulin

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.

Clinical Pearls

• In mouse model of prostate cancer with bone metastases, cabozantinib inhibited tumor growth and tumor cell death
• Results of two preclinical studies indicate that eribulin may have antimetastatic effects
• In a mouse cell model, ibrutinib inhibited adhesion and migration of malignant MCL cells

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.

Ibrutinib Reduces Lymph Node Tumor Burden in Mouse Model

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.

REFERENCES

1. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial.J Clin Oncol. 2013;31(4):412-419.
2. Graham TJ, Box G, Attard G, et al. Multimodality imaging investigation of response to cabozantinib in a VCaP model of prostate bone metastasis. Presented at American Association for Cancer Research Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract 3924.
3. McCracken PJ, Ito K, Yanagimachi M, et al. Eribulin alters vascular function in human triplenegative (TN) breast MX-1 and MDA-MB-231 tumor xenograft models as measured by DCEMRI. Presented at American Association for Cancer Research Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract 4502.
4. Dezso Z, Oestreicher J, Weaver A, et al. Gene expression profiling (GEP) reveals epithelial mesenchymal transition (EMT) genes selectively differentiating eribulin sensitive breast cancer cell lines. Presented at American Association for Cancer Research Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract 1522.
5. Chang BY, Francesco M, Steggerda S, et al. Ibrutinib inhibits malignant cell adhesion and migration and reduces tumor burden in lymph node and bone marrow in a murine model of mantle cell dissemination and progression. Presented at American Association for Cancer Research Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract 923.