Methods for treating cancer
a cancer and cancer technology, applied in the field of cancer treatment methods, can solve the problems of many patients relapse with drug-resistant breast cancer, inability to stop the ovaries, and limited utility of fulvestran
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Test Compounds
[0154]RAD1901 used in the examples below was (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride, manufactured by IRIX Pharmaceuticals, Inc. (Florence, S.C.). RAD1901 was stored as a dry powder, formulated for use as a homogenous suspension in 0.5% (w / v) methylcellulose in deionized water, and for animal models was administered by oral gavage. Tamoxifen, raloxifene and estradiol (E2) were obtained from Sigma-Aldrich (St. Louis, Mo.), and administered by subcutaneous injection. Fulvestrant was obtained from Tocris Biosciences (Minneapolis, Minn.) and administered by subcutaneous injection. Other laboratory reagents were purchased from Sigma-Aldrich unless otherwise noted.
Cell Lines
[0155]MCF-7 cells (human mammary metastatic adenocarcinoma) were purchased from American Type Culture Collection (Rockville, Md.) and were routinely maintained in phenol red-free minimal essential me...
example i
RAD1901-Everolimus Combinations Provided Enhanced Tumor Growth Inhibition in Tumor and / or Cancer Expressing WT ER or Mutant ER (e.g., Y537S), with Different Prior Endocrine Therapy
[0169]I(A). Effectiveness of RAD1901 on animal xenografts models
[0170]I(A)(i) RAD1901 inhibited tumor growth in PDx models (PDx-1 to PDx-12) regardless of ER status and prior endocrine therapy
[0171]FIG. 1 demonstrates tumor growth inhibition effects in various PDx models for mice treated with RAD1901 alone. Twelve patient-derived xenograft models were screened to test RAD1901 response in a variety of genetic backgrounds with varied levels of ER, PR and Her2. Full efficacy study was carried out for PDx models marked with “*” (PDx-1 to PDx-4, and PDx-12), with n=8-10. Screen study was carried out for other PDx models (PDx-5 to PDx-11), with n=3. The PDx models were treated with vehicle (negative control) or RAD1901 at a dosage of 60 mg / kg for 60 days p.o., q.d. As demonstrated in FIG. 1, PDx models in which ...
example ii
RAD1901 Preferably Accumulated in Tumor and Could be Delivered to Brain
[0216]MCF-7 xenografts as described in Example I(A)(i) were further evaluated for RAD1901 concentration in plasma and tumor using LC-MS / MS. At the end of study, the concentration of RAD1901 in plasma was 344±117 ng / mL and in tumor in 11,118±3,801 ng / mL for the 60 mg / kg dose level. A similar tumor to plasma ratio was also observed at lower dose levels where tumor concentrations were approximately 20-30 fold higher than in plasma. RAD1901 levels in plasma, tumor, and brain for mice treated for 40 days are summarized in Table 1. A significant amount of RAD1901 was delivered to the brain of the treated mice (e.g., see the B / P ratio (RAD1901 concentration in brain / the RAD1901 concentration in plasma)), indicating that RAD1901 was able to cross the blood-brain barrier (BBB). Unexpectedly, RAD1901 preferably accumulated in the tumor. See, e.g., the T / P (RAD1901 concentration in tumor / RAD1901 concentration in plasma) rat...
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