Bristol-Myers Squibb Dasatinib Src Inhibition in Endometrial Cancer

Endometrial cancer is the most common of the gynecologic malignancies; affecting 42,160 women in the US in 2009.1 In addition it is often a hormonally driven tumor, expressing in many cases both estrogen receptor (ER) and progesterone receptor (PR). While most endometrial cancers are treated successfully with surgery, there is still a need for new agents in the treatment of advanced or recurrent disease. One potential agent is dasatinib, since its target, Src Family Kinases (SFKs), has been implicated in the genesis of the disease. Although not extensive, increasing evidence indicates a link between SFKs and endometrial cancer. In addition one study in breast cancer presented at the American Society of Clinical Oncology (ASCO) in 2009 demonstrated that patients with ER positive breast tumors have a higher response rate to dasatinib, suggesting perhaps a synergy between hormonal therapy and dasatinib. Because of its high efficacy for inhibiting SFKs and growth of the tumor vasculature, as well as a possible effects on the ER, dasatinib is an exciting new possibility for treatment of endometrial cancers.

Questions regarding the ability of dasatinib to inhibit its primary target in tumor tissue (regardless of cancer type) and the relationship between inhibition of SFKs in tissue vs. SFKs in blood cells are also unresolved, as few correlative studies have accompanied the plethora of clinical trials assessing the efficacy of the drug in patients. Furthermore, the effect of dasatinib on the stability of the estrogen receptor in those tissues expressing the receptor (uterine and breast, particularly) is also unknown. Src kinase has been shown to physically associate with the ER and to mediate some of its rapid signaling effects in the presence of estrogen.6 If this physical association also stabilizes the receptor (which is normally degraded upon estrogen stimulation), dasatinib could affect estrogen receptor signaling in an indirect manner. In the Mayer study, all 9 controlled tumors were ER/PR+, suggesting a possible relationship between ER expression and dasatinib response.33 These are questions unexplored in patients. The goals of this study, therefore, are to address these questions and to provide insights for all appropriate cancer types into the action of dasatinib on SFK alone and on the ER in patient samples exposed to the drug. Furthermore, if inhibition of SFKs in blood cells correlates with that in tissue, future studies can utilize blood samples instead of or in addition to tissue to monitor dasatinib activity, obviating the need for extra biopsies or surgical samples for such analyses. The investigators therefore propose a Phase 0 study of dasatinib in patients with endometrial cancer who are undergoing planned hysterectomy. The purpose of this trial will not be therapeutic; the endpoints will be translational as per the Phase 0 design. Due to the potential relationship with ER expression, only endometrioid tumors will be studied, as they most frequently express this receptor (as opposed to clear cell or serous histologies, which most often do not express ER and are not estrogen related).

Given the extensive safety data now available for dasatinib the investigators plan to allow dosing up to the accepted Maximum Tolerated Dose(MTD) which is being used across the dasatinib program. Based on the preliminary data from the Blackwell trial in breast cancer34, adequate inhibition of src family kinases is questionable at doses even higher than 100 mg (although this study was done at steady-state after 4 weeks of treatment); thus it is unlikely that doses less than 100 mg will have any value. The investigators therefore plan to begin at 100 mg to demonstrate safety (and perhaps measurable src inhibition) and then escalate to 200 mg (which is more likely to result in measurable levels of interest) assuming safety. If feasible the investigators would anticipate the ability to demonstrate a dose response of our assay in both tissue and blood, which also requires testing two doses.