METHOD OF TREATING CANCER WITH TELOTRISAT OR A PRODRUG THEREOF
Provided herein are methods of treating cancer with a TPH1 inhibitor. In certain embodiments, methods are provided which display remarkable efficacy and bioavailability for the treatment of certain tumors, for example, a neuroendocrine tumor in a human patient. In certain embodiments, the methods comprising treating the patient with telotristat, a telotristat prodrug, or a pharmaceutically acceptable salt thereof, which can be administered either alone or in combination with other anticancer or antidiarrheal agents.
1 . A method of treating cancer in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a tryptophan hydroxylase 1 (TPH1) inhibitor, wherein the TPH1 inhibitor is telotristat, a telotristat prodrug, or a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 , wherein the TPH1 inhibitor reduces the growth rate of a neuroendocrine tumor in a patient.
3 . The method of claim 2 , wherein the neuroendocrine tumor expresses high levels of TPH1 activity relative to reference cells.
4 . The method of claim 2 , the method further comprising:
screening the neuroendocrine tumor for TPH1 messenger ribonucleic acid (mRNA) level; and
approving the patient for TPH1 inhibitor treatment only when the TPH1 mRNA level of the neuroendocrine tumor is at least 30 times that of the reference cells.
5 . The method of claim 4 , wherein the TPH1 mRNA level is at least 60 times that of the reference cells.
6 . The method of claim 4 , wherein the TPH1 mRNA level is at least 100 times that of the reference cells.
7 . The method of claim 4 , wherein the reference cells are HeLa cells.
8 . The method of claim 2 , the method further comprising:
screening the neuroendocrine tumor by a Ki-67 index test; and
approving the patient for TPH1 inhibitor treatment only when the Ki-67 index is no greater than 20%.
9 . The method of claim 8 , wherein the method comprises approving the patient for TPH1 inhibitor treatment only when the Ki-67 index is no greater than 3%.
10 . The method of claim 8 , wherein the method comprises approving the patient for TPH1 inhibitor treatment only when the Ki-67 index is no greater than 1%.
11 . The method of claim 1 , further comprising concurrently treating the patient with an antitumor agent.
12 . The method of claim 11 , wherein the antitumor agent is gemcitabine, cisplatin, paclitaxel, a paclitaxel derivative, or a combination thereof.
13 . The method of claim 12 , wherein the antitumor agent is a combination of gemcitabine and cisplatin.
14 . The method of claim 12 , wherein the antitumor agent is a combination of albumin and paclitaxel.
15 . The method of claim 12 wherein the antitumor agent is nab-paclitaxel.
16 . The method of claim 1 , further comprising concurrently treating the patient with a somatostatin analog (SSA).
17 . The method of claim 1 , wherein the telotristat prodrug is telotristat ethyl.
18 . The method of claim 1 , wherein the pharmaceutically acceptable salt is a hippurate.
19 . The method of claim 1 , wherein the TPH1 inhibitor is telotristat ethyl hippurate.
20 . The method of claim 1 , where the cancer is biliary tract cancer, bladder cancer, breast cancer, prostate cancer, small-cell lung cancer, or a combination thereof.
21 . The method of claim 20 , where the biliary tract cancer is cholangiocarcinoma.
22 . The method of claim 1 , where the patient experiences carcinoid-syndrome-related diarrhea.
23 . The method of claim 1 , where the patient does not experience carcinoid-syndrome-related diarrhea.
24 . The method of claim 1 , wherein the TPH1 inhibitor dose is from 100 to 500 mg.
25 . The method of claim 1 , wherein the TPH1 inhibitor dose is about 250 mg.
26 . The method of claim 1 , wherein the TPH1 inhibitor dose is administered from one to five times per day.
27 . The method of claim 1 , wherein the TPH1 inhibitor dose is administered three times per day.