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Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer Kohei Otsubo,1 Kaname Nosaki,2 Chiyo K. Imamura,3 Hiroaki Ogata,1 Akitaka Fujita,1 Shinya Sakata,1 Fumihiko Hirai,2 Gouji Toyokawa,2 Eiji Iwama,1 Taishi Harada,1 Takashi Seto,2 Mitsuhiro Takenoyama,2 Takeshi Ozeki,4 Taisei Mushiroda,4 Mieko Inada,5 Junji Kishimoto,5 Kenji Tsuchihashi,6 Kentaro Suina,6 Osamu Nagano,6 Hideyuki Saya,6 Yoichi Nakanishi1,5 and Isamu Okamoto1 1 Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka; 2Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka; 3Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, Tokyo; 4 Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama City; 5Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka; 6Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
Key words Cancer stem cell, CD44v, non-small-cell lung cancer, oxidative stress, salazosulfapyridine Correspondence Isamu Okamoto, Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel: +81-92-642-5378; Fax: +81-92-642-5390; E-mail: [email protected] Funding Information Japan Agency for Medical Research and Development (16lm0103008j0005), Eli Lilly Japan. Received May 3, 2017; Revised June 20, 2017; Accepted June 27, 2017 Cancer Sci 108 (2017) 1843–1849 doi: 10.1111/cas.13309
Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(–) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-na€ıve patients with advanced non-squamous nonsmall-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary endpoint was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin–pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin–pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854.
ancer stem cells constitute a small population of cancer cells that are capable of self-renewal and cancer initiation.(1) Cancer stem cells are also more resistant to cancer treatments, including chemotherapy and radiation therapy, than are other cancer cells.(2,3) Treatment strategies that target CSCs are therefore being pursued in order to improve outcomes in cancer patients. Markers for CSCs are thought to include CD44, CD133, CD90, and aldehyde dehydrogenase, but no agents that specifically target CSCs have yet been established.(4) CD44 is an adhesion molecule for the ECM and is implicated in various physiological and pathological processes, including tumor cell growth, invasion, and metastasis.(5,6) It has also been identified as a cell surface marker for CSCs of solid tumors.(5) Splice variant isoforms of CD44 are expressed in various tumors(7–10) and have recently been found to bind to xCT, a subunit of a cystine-glutamate antiporter known as system xc(–). Such binding stabilizes expression of this transporter system at
the cell surface and thereby promotes the intracellular synthesis of the antioxidant GSH from imported cystine. Expression of CD44v in tumor cells thus confers resistance to oxidative stress and thereby promotes tumor growth and treatment resistance.(11) The stem cell-like characteristics of CD44v-positive cancer cells are dependent on xCT-mediated cystine transport and consequent upregulation of the GSH-dependent antioxidant system for maintenance of cellular redox homeostasis. Non-small-cell lung cancer is the leading cause of cancer-related mortality worldwide.(12) The standard first-line treatment for advanced NSCLC has long been platinum-based combination chemotherapy, with the goal of prolongation of life and relief of symptoms.(13,14) Recently, however, the identification of driver oncogenes, such as those encoding mutant forms of EGFR and fusions of ALK, has led to the development of targeted agents such as EGFR-TKIs and ALK-TKIs that have proven superior to chemotherapy for first-line management of patients with advanced NSCLC positive for these
determined to be the RD if six patients had been treated at that dose level; however, if only three patients had been treated at that dose level, another three patients were enrolled and this dose level was determined as the RD, unless DLT was observed in more than one of six patients. Patients who experienced DLT discontinued study medication. After four cycles of combination therapy with CDDP, PEM, and SASP, patients without disease progression were eligible for maintenance therapy with PEM and SASP every 21 days. Salazosulfapyridine was given for up to 365 days. The trial was carried out in compliance with the study protocol, the Declaration of Helsinki, and Japanese Good Clinical Practice guidelines. All patients provided written informed consent. The trial was carried out at Kyushu University Hospital and National Kyushu Cancer Center (both Fukuoka, Japan) after the protocol was approved by each institutional review board and registered as UMIN000017854. Study group. Adult (≥20 years of age) patients with pathologically confirmed stage IIIB or IV non-squamous NSCLC, an ECOG performance status of 0 or 1, and adequate organ function were eligible for the study. Individuals who had previously received cytotoxic chemotherapy for NSCLC were excluded from the trial, although previous treatment with EGFR-TKIs for EGFR mutation-positive patients or with ALK-TKIs for ALK fusion-positive patients was allowed. Individuals with symptomatic brain metastases were excluded, as were those with spinal metastasis requiring irradiation or surgery. Patients with asymptomatic brain metastasis were eligible. Patients who underwent palliative radiotherapy for metastatic lesions or surgery under general anesthesia within 14 days before enrollment were excluded. Efficacy assessment. Objective tumor response was assessed according to RECIST (version 1.1)(20) every 6 weeks for the first 6 months and every 9 weeks thereafter. Progression-free survival was assessed for each patient who received at least one dose of SASP. Pharmacokinetic analysis. For pharmacokinetic analysis, the first individual dose of SASP on day 1 was administered orally together with 200 mL water after the patients had fasted overnight, with a meal being permitted after blood sampling at 4 h after the drug was given. Blood samples were obtained before and at 0.5, 1, 2, 3, 4, 6, 9, 12, and 24 h after SASP administration. The other two doses of SASP were not given on day 1. Plasma was prepared from blood by centrifugation and was stored at 20°C until analysis. The plasma concentration of SASP was determined by a validated ultraperformance liquid chromatography and tandem mass spectrometry method.(21) The AUC0–24 for SASP was calculated according to the linear trapezoidal rule. Genotyping of ABCG2 and NAT2. The single nucleotide polymorphism rs2231142 in ABCG2 (421C?A, Q141K) and NAT2 genotype (NAT2*4, *5B, *6A, *7B), both of which affect the pharmacokinetics of SASP, were evaluated by direct sequencing of genomic DNA isolated from blood samples. Measurement of free CD44v protein level in serum. Serum samples collected from 14 patients before treatment and on day 21 of treatment cycle 1 were tested with ELISA for human CD44v9 (Cosmo Bio, Tokyo, Japan). The amount of free CD44v in serum was calculated relative to the absorbance of 1 lL culture supernatant of the CD44v9-positive cell line OSC 19 as 1 unit. Statistical analysis. The primary end-point of the study was the percentage of patients who experienced DLT. Secondary end-points included adverse events, pharmacokinetics of SASP, Cancer Sci | September 2017 | vol. 108 | no. 9 | 1844
Original Article Otsubo et al.
response rate, and PFS. Changes in the serum level of free CD44v protein were assessed with the paired Student’s t-test as performed with SAS software version 9.3 (SAS Institute, Cary, NC, USA). A P-value of < 0.05 was considered statistically significant. Results Patient characteristics. Fifteen patients at two institutions were enrolled in the study between April 2015 and February 2016. The demographics and clinical characteristics of the study participants are shown in Table 1. The median age was 66 years (range, 42–74 years), 10 patients were men, and 14 individuals had stage IV disease. EGFR mutation status was evaluated in all patients, five of whom were found to harbor activating EGFR mutations (exon 19 deletions or L858R in exon 21) and had been previously treated with EGFR-TKIs. One patient was positive for the EML4-ALK fusion gene and had been previously treated with crizotinib and alectinib. Maximum tolerated dose and DLT. Allocation of patients to treatment during the study is summarized in Figure 1, and DLTs apparent at each dose level are listed in Table 2. Doselimiting toxicity was not observed in the first three patients treated at dose level 1. At dose level 2, the first patient experienced hives of grade 3 at 9 days after the onset of SASP treatment, and this condition was ameliorated immediately after discontinuation of SASP. The external Efficacy and Safety Review Committee recommended that the patient be excluded
from DLT assessment because the hives were regarded as an incidental adverse event. The subsequent three patients at dose level 2 did not experience DLT. At dose level 3, two of three patients experienced DLT (anorexia of grade 3). According to the protocol, two additional patients were enrolled at dose level 2, and two of the total of five patients treated at this dose level experienced DLT (hypotension or pneumonitis, each of grade 3). To confirm the safety of dose level 1, three additional patients were enrolled, with one of the total of six patients treated at this dose level experiencing DLT (elevation of aspartate and alanine aminotransferase levels, each of grade 3). The MTD and RD of SASP, when given in combination with full-dose CDDP and PEM, were therefore determined to be 3 and 1.5 g/day, respectively. All DLTs were reversible after additional treatment or discontinuation of SASP. Safety profile of combination therapy with CDDP, PEM, and SASP. Fifteen patients received combination therapy with
CDDP, PEM, and SASP. The median number of treatment cycles was two (range, 1–17 cycles), and the median duration of SASP treatment was 45 days (range, 8–365 days). The most frequent drug-related adverse events (all CTCAE grades) during protocol treatment were anorexia (n = 14), fatigue (n = 14), nausea (n = 12), anemia (n = 10), vomiting (n = 9), constipation (n = 9), leukopenia (n = 9), and neutropenia (n = 9) (Table 3). Adverse events of grade 3 or 4 observed in ≥20% of patients included neutropenia (n = 8), hyponatremia
Table 1. Characteristics of patients with non-small-cell lung cancer treated with salazosulfapyridine in combination with cisplatin and pemetrexed (n = 15) Characteristics Age, years Median Range Sex, n (%) Male Female ECOG performance status, n (%) 0 1 Clinical stage, n (%) IIIB IV Histology, n (%) Adenocarcinoma Smoking status, n (%) Never smoked Ex-smoker Current smoker Gene mutation status, n (%) None EGFR L858R EGFR Ex19del EML4-ALK Prior treatment, n (%) None Gefitinib Afatinib Crizotinib and alectinib
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Original Article SASP targeting cancer stem cells in NSCLC
Table 3. Frequency of drug-related adverse events in patients with advanced non-small-cell lung cancer during protocol treatment with salazosulfapyridine (SASP) in combination with cisplatin and pemetrexed SASP dose (g/day) 1.5 (n = 6) All grades Non-hematologic Anorexia Fatigue Nausea Vomiting Constipation Hyponatremia ALT increased AST increased GGT increased Stomach ache Hypotension Pneumonitis Febrile neutropenia Hematologic Anemia Leukopenia Neutropenia Thrombocytopenia
Data are shown as n (%). ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, c-glutamyl transpeptidase.
(n = 7), leukopenia (n = 6), and anorexia (n = 4). There were no treatment-related deaths. Pharmacokinetics of SASP. The Cmax of SASP after the first single dose on day 1 at levels 1, 2, and 3 ranged from 7.1 to 24.8 lg/mL, from 8.5 to 39.2 lg/mL, and from 6.5 to 13.9 lg/ mL, respectively (Table 4). The AUC0–24 after the first single dose on day 1 at levels 1, 2, and 3 ranged from 55.2 to 235.5 lg/h/mL, from 102.8 to 477.4 lg/h/mL, and from 49.1 Table 4. Pharmacokinetic parameters of salazosulfapyridine and genotypes of ABCG2 and NAT2 in patients with advanced non-smallcell lung carcinoma Dose level 1
to 158.4 lg/h/mL, respectively. Both Cmax and AUC0–24 thus varied markedly among individuals within each dose level. High AUC0–24 values for SASP were apparent in patients with two reduced-function alleles of ABCG2 (A/A) or NAT2 (*6A/ *6A or *6A/*7B).(22) In addition, exposure to SASP did not correspond to the occurrence of DLT. Efficacy. Two of 15 patients were not evaluable for objective response according to RECIST because they had no post-treatment tumor measurement. Among the 13 assessable patients, four individuals showed a partial response (two at dose level 1, two at dose level 2), yielding an overall response rate of 26.7%. An additional seven patients (46.7%) experienced stable disease, yielding a disease control rate of 73.3%. Median PFS for all 15 patients was 11.7 months (Fig. 2a). At the time of data analysis, 11 of the 15 patients were alive, yielding a 1-year survival rate of 73%. Analysis of free CD44v protein in serum. Serum was obtained from 14 patients both before treatment and on day 21 of cycle 1 for measurement of free CD44v protein level. The CD44v level after the first treatment cycle was significantly higher than that before treatment (Fig. 2b). Discussion
The efficacy of cancer therapies including cytotoxic chemotherapy and radiation therapy is attributable in part to the production of reactive oxygen species and the consequent induction of oxidative stress in cancer cells.(2) Variant isoforms of CD44 have recently been found to stabilize the cystine transporter subunit xCT and thereby to promote intracellular formation of the antioxidant GSH and consequent chemoresistance in cancer cells.(11) Given that CD44 is a CSC marker, the CD44v–xCT complex is thought to play an important role in chemoresistance in CSCs. This complex is Cancer Sci | September 2017 | vol. 108 | no. 9 | 1846
Original Article Otsubo et al.
Fig. 2. (a) Progression-free survival (PFS) for all study patients with advanced non-small-cell lung cancer treated with salazosulfapyridine in combination with cisplatin and pemetrexed (n = 15). (b) Serum level of free CD44 variant (CD44v) before treatment and at day 21 of treatment cycle 1 for 14 of the study patients. **P < 0.01 (paired Student’s t-test).
therefore considered a potential novel target for therapy directed against CSCs. Salazosulfapyridine, a drug commonly used to treat ulcerative colitis and rheumatoid arthritis, is a well-characterized specific inhibitor of xCT.(17,18) Given that SASP has shown efficacy for treatment of CD44v-positive tumors in animal models,(23) it is a potential anticancer drug for targeting of CSCs. This was a phase I trial of SASP in combination with standard chemotherapy for non-squamous NSCLC. The primary objective of our trial was to determine the RD of SASP. Our results show that SASP combined with standard-dose CDDP and PEM has a manageable safety profile when given at dose level 1 (1.5 g/day). Two of three patients experienced anorexia of grade 3 as a DLT at dose level 3 (4.5 g/day), despite adequate prophylactic treatment with anti-emetic agents. The common adverse events of SASP are gastrointestinal toxicity (nausea, vomiting, gastrointestinal upset, diarrhea, and stomach cramps), fatigue, and headache.(24) It is possible that the observed anorexia reflected synergistic toxicity for the combination of SASP and CDDP. One patient treated at dose level 2 (3 g/day) experienced pneumonitis of grade 3 as a DLT. Although respiratory disorders are not common adverse events of SASP treatment, SASP has previously been implicated in the development of pneumonitis.(25) Hypotension of grade 3, which has previously been reported as a severe sideeffect of SASP, was observed as a DLT in one patient at dose level 2. The occurrence of DLT for this combination therapy was independent of SASP exposure as reflected by AUC0–24 and Cmax. Only approximately one-third of an oral dose of SASP is absorbed by the intestine. The remaining drug is metabolized by intestinal bacteria to 5-aminosalicylic acid and sulfapyridine, which have no effect on xCT. Sulfapyridine is relatively well absorbed from the intestine and further metabolized by NAT2 in the liver, whereas 5-aminosalicylic acid is absorbed to a much lesser extent. Breast cancer resistance protein, which is an ATP-binding cassette transporter encoded by ABCG2, restricts intestinal SASP absorption. Similar to the results of a previous phase I study of SASP monotherapy,(21) exposure to SASP after oral doses of 1.5–4.5 g/day in the present study was not dose-dependent, likely reflecting genetic polymorphism of ABCG2 and NAT2. A previous phase I/II study of SASP in patients with recurrent or progressive glioma found no tumor shrinkage after treatment at a dose of 1.5–6 g/day.(26) A more recent phase I study of SASP at a dose of 8–12 g/day in previously treated patients with advanced gastric cancer also detected no tumor shrinkage.(21) In our present phase I study, the response rate (26.7%) according to RECIST did not differ from that previously observed for chemotherapy with CDDP and PEM in patients advanced NSCLC. However, the median PFS of
11.7 months in our study was substantially longer than that (4.0–5.3 months) reported in previous studies of CDDP and PEM for non-squamous NSCLC.(27–30) Given that tumor relapse after chemotherapy is thought to be driven by CSCs,(1) a reduction in the number of CSCs induced by SASP treatment may prolong time to relapse. Indeed, immunohistochemical analysis of tumor tissue obtained before treatment in the present study revealed that the median PFS of patients (n = 5) with a high proportion of CD44v-positive cells was longer than that of those (n = 8) with a low proportion (>12 vs. 7.9 months), despite the lack of a confirmed partial response in the former patients. Although similar evaluation with a larger sample size is warranted, these data suggest that the proportion of CD44v-positive cells is a potential predictive biomarker for SASP treatment. The precise mechanism of CD44v release and the origin of circulating CD44v are not known, although CD44v may be released in at least two distinct types of vesicles, apoptotic blebs and exosomes.(31) The adhesion molecule L1 has been shown to be cleaved in exosomes and apoptotic membrane vesicles released from ovarian cancer cells undergoing apoptosis.(32) Cleavage of CD44 also occurs in exosomes(33) and might be induced by apoptotic stimuli.(34) Together, these observations suggest that CD44v might be cleaved in and enter plasma by way of apoptotic blebs and exosomes released from CD44v-positive stem-like cancer cells undergoing apoptosis. Consistent with our data, SASP treatment was previously associated with a decrease in the number of CD44v-positive cells in post-treatment tumor tissue of patients with advanced gastric cancer.(21) It is thus possible that the prolonged PFS observed in the present study was due to a SASP-induced reduction in the number of CD44v-positive CSCs that are the origin of disease recurrence. In conclusion, we found that SASP was safe at the RD of 1.5 g/day in combination with CDDP and PEM. Our results suggest that this triplet regimen may prolong PFS compared with that achieved with CDDP and PEM alone. Given that only approximately one-third of SASP given orally is absorbed by the intestine, and that the remaining drug induces gastrointestinal toxicity, an i.v. injectable, water-soluble form of the drug is now under development in order to reduce such toxicity and to facilitate maintenance of an effective blood concentration of SASP. Further development of additional agents that target the CD44v–xCT complex is also warranted to evaluate the efficacy of CSC-targeted therapy as a novel treatment strategy.
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Acknowledgments This study was supported by AMED (Translational Research Network Program) of the Japan Agency for Medical Research and Development (grant no. 16lm0103008j0005). Pemetrexed was kindly provided by Eli
Original Article SASP targeting cancer stem cells in NSCLC Lilly Japan. We thank Toshihiko Doi (Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Japan) and Jiichiro Sasaki (Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara City, Japan) as members of the external Efficacy and Safety Review Committee, as well as Koji Todaka, Ritsuko Taketomi, and other staff of the Center for Clinical and Translational Research, Kyushu University Hospital, for data collection, analysis, and interpretation, as well as helpful advice.
Disclosure Statement The authors have no conflict of interest.
area under the concentration–time curve from 0 to 24 h spliced variant isoforms of CD44 cisplatin maximum plasma concentration cancer stem cell dose-limiting toxicity epidermal growth factor receptor glutathione maximum tolerated dose N-acetyltransferase 2 non-small-cell lung cancer pemetrexed progression-free survival recommended dose salazosulfapyridine tyrosine kinase inhibitor
anaplastic lymphoma kinase
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Supporting Information Additional Supporting Information may be found online in the supporting information tab for this article: Fig. S1. Time course of the volume of tumors formed by HCT116 p53 / cells in nude mice treated with CDDP (2 mg/kg) plus SASP (50, 100, 200, or 400 mg/kg). CDDP was injected intraperitoneally 5, 8, and 11 days after subcutaneous injection of 2 9 106 cells. SASP or saline was injected intraperitoneally once daily from days 5 to 10. Data are means SEM for 5 mice per group.
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