In the past 30 years, treatment of advanced non- small cell lung cancer,
significant progress , 98% of the extensive stage SCLC (ED-SCLC) still
die of the disease. In recent years, biological targeted therapy has the
potential to improve small- cell lung cancer to provide a broader space
. At present, a number of clinical trials dedicated to research those that interfere with small cell lung cancer
biological signal transduction pathway of small molecules in order to
alter the disease process. Including protease inhibitors (BI) bortezomib
, anti-angiogenic drug thalidomide , bevacizumab, and a variety of
tyrosine kinase inhibitors (TKIs). ( A ) CCI-779 (temsirolimus)
2005 report , CCI-779 is m-TOR ( target of rapamycin mammalian protein ) kinase inhibitor , m-TOR signaling on tumor cells , and a variety of cell functions downstream of tyrosine kinase receptors a core role in signal transduction regulation . It is also a nutrient sensor, control of protein synthesis and cell proliferation, and adjust the various angiogenic cytokines precursors . When CCI-779 combination with the cytoplasmic protein FKBP , can inhibit the m-TOR, block intracellular signal transduction pathways that regulate cell growth inhibition of a variety of key protein synthesis cycle , the cell cycle in the G1 phase were abolished , thereby inhibiting tumor cell proliferation. ED-SCLC received standard treatment, the median survival was 9 months. 87 cases of patients completed induction chemotherapy (CCI-779 + CBP + VP16) were randomized into the CCI-779 25mg and 250mg two dose groups were intravenously 30 minutes once a week, until disease progression , with a median survival of 19.8 months different dose groups were 16.5 months and 19.8 months , PFS median 4.7 months and 6.3 months to 8.9 months. Above shows the CCI-779对treatment of SCLC have some effect , it is worth further study.
( Two ) bevacizumab
ECOG has reported 2004.6 ~ 2006.8 carried E3501 Phase Ⅱ clinical trial of 39 evaluable enrolled patients receiving first-line treatment were analyzed extensive stage SCLC , treatment options cisplatin + VP16 + bevacizumab , which reached CR 4 cases , PR23 cases, efficiency 69% , patient survival at 6 months was 33% . In the test group did not occur > 2 degrees hemoptysis events.
CALGB30306 Ⅱ clinical trial in 2005,3 ~ 2006,4,72 patients with untreated extensive-stage SCLC patients according to inclusion criteria involved in the clinical trial program for the cisplatin + CPT11 + bevacizumab . The results did not occur > 2 degrees hemoptysis adverse reactions. In evaluable patients , 2 cases of CR (3%), 42例PR (59%) RR was 80% , with a median survival of 10.6 months , PFS 7 months.
Genentech reports Ⅱ clinical trials , patients were untreated into the group 's limited- SCLC, programs for the concurrent chemoradiotherapy , chemotherapy is CPT11 + carboplatin + bevacizumab . After the end of chemotherapy , maintenance therapy with bevacizumab to six months. Entry into the study group , 29 patients, 2 cases of serious adverse events occurred , that tracheoesophageal fistula , one case died as a result . The third case of gas accumulation and upper gastrointestinal bleeding, after death, but for unknown reasons. The three cases of adverse events occurred in the bevacizumab maintenance treatment period, and all patients with persistent esophagitis .
( Three ) VEGFR inhibitor
VEGFR tyrosine kinase channel plurality of small molecule inhibitors also SCLC clinical trials conducted in patients . Including sorafenib , AZD2171, Sunitinib and ZD6474 and so on.
ZD6474 in Canada, the National Cancer Research Centre (CAN-NICIL-BR20) Phase Ⅱ clinical study conducted in 107 patients with previously untreated SCLC patients after chemotherapy or radiation into the group , including 46 cases of limited stage , 61 cases for a wide range of study programs divided into two groups , namely the maintenance therapy, a group taking ZD6474, another group of placebo , the median PFS results of the two groups and no significant difference in overall survival .
AZD2171 (Cediranib) inhibit VEGFR-1, -2 and -3 tyrosine kinase phosphorylation .
2008 Ramalingam have been reported for AZD2171 Phase Ⅱ clinical trial who were enrolled after platinum-based chemotherapy after disease progression in SCLC, 13 patients solution of AZD2171, 30mgQD, 4 weeks for a period , the median treatment period of 2, the main toxicities were fatigue , diarrhea, skin rash and hypertension , efficacy evaluation without PR, 8例SD, median PFS8 weeks. Disease progression after treatment , circulating endothelial cells (CEC) count increased plasma VEGF levels increased. Therefore, further recommendations should be combined with chemotherapy treatment.
Thalidomide has been shown in experiments on SCLC with anti- angiogenesis and apoptosis. 2007 Report thalidomide Ⅱ clinical trials CWRU-1502, into the group by extensive stage SCLC, after standard chemotherapy, achieved CR or PR after , and then enter the thalidomide maintenance therapy. Median survival of 13 months (95% C1 10 ~ 16 months ) , 1 -year survival 52% (95% C1 32.5 ~ 67.9 months ) .
LLCG research report in 2007 , the Phase Ⅲ clinical trial patients are extensive stage SCLC, randomization , research programs divided into two groups , one group of VP16 + carboplatin + thalidomide , another group of VP16 + carboplatin + placebo. From 2003 to 2006, 724 cases enrolled 365 patients randomized into the containing thalidomide , 359 cases into with the placebo group , the results were similar overall survival time , 2-year survival rates were 13%. The median survival was 10.2 months and 10.5 months (P0.24), PFS no difference. In the thalidomide group of major adverse events pulmonary embolism anddeep vein thrombosis ( Four ) Src tyrosine kinase inhibitor
Src family proteins from various non- receptor tyrosine kinase regulatory signals , including tumor cell surface molecules , G protein binding receptor , growth factors and adhesion factors molecules. Src family , including c-Src, Yes, Yrk, Fyn, Lyn, Hck, Lck, Fgr and BIKSrc family genes mostly in blood cells, but c-Src, Fyn and Yes in different tissues, such as epithelial cells. Lung cancer cell lines and tumor tissues by immunoblotting and immunohistochemical expression of c-Src can be displayed . SCLC, adenocarcinoma and squamous cell carcinoma are also overexpression of c-Src , but not found in normal lung tissue .
Dasatinib (BMS354825) is a tyrosine kinase phosphorylation inhibitor which can block the phosphorylation of Src kinase and phosphorylation of other kinases, including c-Src, Lck, Fyn, Yes, Abl, c-kit and EphA2. Dasatinib inhibits cell cycle , blocking the G1 → S phase , mainly through the Rb gene and P27 products dephosphorylation . CALGB30602 dasatinib clinical trials primarily used for sensitive relapsed SCLC.
AZD0530 has a pair of c-Src and c-Abl inhibition , has been carried out Ⅱ clinical trials , mainly for patients with extensive-stage SCLC after four cycles of chemotherapy .
( Five ) class of recombinant molecules
N901 is a recombinant molecule of murine anti- CD56 monoclonal antibody covalently coupled to ricin molecule , SCLC tumor cell surface CD56 epitope , which is the natural neural cell adhesion molecule , a target point of treatment N901 . Treatment with N901 SCLC, 1 patients had clinical effect , but all patients participating in the study have murine antibody and its ricin has limitations immune response. Has been modified to fully humanized antibody , and which is coupled to an new substances , the United Almond (Maytasinoid) effective molecules , called DM-1, a beauty Almond microtubule depolymerization complexes. Recombinant molecule now known BB10901 or humanized N901-DM1, Ⅱ clinical trial enrolled patients with recurrent SCLC, if their cancer cell surface CD56 expression , try BB10901, for the first time into the group of 10 patients, 2 cases of PR, currently still in progress.
( Six ) apoptotic molecules
When the adjustment is lost with SCLC apoptosis Bcl-2 expression , which means the continued survival of tumor cells , and tumor resistance to chemotherapy . In human SCLC with high expression of Bcl-2 80%. Preclinical studies have shown that antisense oligonucleotides can target Bc1-2 mRNA levels of Bcl-2 inhibition . Therefore, inhibitors of Bcl-2 has a higher potential targeting ability and high specificity . Small molecule inhibitors of Bcl-2 SCLC cell lines available on the dramatic anti- tumor effect.
Blimersen (G3139) is the Bcl-2 antisense oligonucleotides inhibit the Bcl-2 level, two clinical studies and a randomized Phase Ⅱ clinical study was conducted Oblimersen combined cytotoxic chemotherapy SCLC, can significantly enhance the standard chemotherapy .
Ⅰ clinical research program for the treatment of recurrent paclitaxel Oblimersen of SCLC, there are two cases of patients originally expected poor prognosis after treatment maintained SD, another one case the disease did not progress to keep six months, but did not observe an effective response .
The second clinical trial evaluated Oblimersen + carboplatin + VP16 extensive first-line treatment of SCLC, 12 cases 10 cases effective, efficient and 83%.
CALGB conducted a phase Ⅱ clinical trial comparing carboplatin + VP16 and carboplatin + VP16 + Oblimersen, results Oblimersen no increase in RR and survival time. Why is there such a result ? Speculate that there is no sufficiently suppressed target Bcl-2 , as measured in peripheral blood did not show Bcl-2 protein levels decrease .
Other related Bcl-2 family of targeted drugs , will soon enter clinical studies . ABT-263 is an oral agent , Bcl-2/Bcl-xL inhibitors will have to be multi-center phase Ⅰ / Ⅱ clinical study for relapsed SCLC. Obatoclax and two AT-101 is another inhibitor of Bcl-2 . Obatoclax + topotecan for relapsed SCLC studies are in progress . NCI ongoing AT-101 monotherapy for relapsed SCLC Phase Ⅱ clinical study.
( Seven ) Hedgehog (Hh) targeted therapy
Hh is the SCLC and embryonic cells ( stem cells ) an important signaling pathway , which regulates stem cells / progenitor cells in different ways , in the Mammalia class animal 's trachea and lung development plays an important role , and to promote SCLC with neuroendocrine differentiation tendencies . Smoothend (Smo) is through a membrane protein , Hh downstream signaling preaching must. When Smo inhibition , can inhibit the Hh pathway activity. Smo inhibition of Hh pathway analogs disinhibition may have a high specificity and potential anti-tumor effect, so the tumor target Smo research direction , when the SCLC patients with high expression of Sonic Hh ligand when , Smo inhibitors can inhibit SCLC. For preparations such as GDC-0449, for the oral administration. Has been carried out Ⅰ clinical safety and determine the treatment dose study . Currently upcoming Phase Ⅱ trial .
2005 report , CCI-779 is m-TOR ( target of rapamycin mammalian protein ) kinase inhibitor , m-TOR signaling on tumor cells , and a variety of cell functions downstream of tyrosine kinase receptors a core role in signal transduction regulation . It is also a nutrient sensor, control of protein synthesis and cell proliferation, and adjust the various angiogenic cytokines precursors . When CCI-779 combination with the cytoplasmic protein FKBP , can inhibit the m-TOR, block intracellular signal transduction pathways that regulate cell growth inhibition of a variety of key protein synthesis cycle , the cell cycle in the G1 phase were abolished , thereby inhibiting tumor cell proliferation. ED-SCLC received standard treatment, the median survival was 9 months. 87 cases of patients completed induction chemotherapy (CCI-779 + CBP + VP16) were randomized into the CCI-779 25mg and 250mg two dose groups were intravenously 30 minutes once a week, until disease progression , with a median survival of 19.8 months different dose groups were 16.5 months and 19.8 months , PFS median 4.7 months and 6.3 months to 8.9 months. Above shows the CCI-779对treatment of SCLC have some effect , it is worth further study.
( Two ) bevacizumab
ECOG has reported 2004.6 ~ 2006.8 carried E3501 Phase Ⅱ clinical trial of 39 evaluable enrolled patients receiving first-line treatment were analyzed extensive stage SCLC , treatment options cisplatin + VP16 + bevacizumab , which reached CR 4 cases , PR23 cases, efficiency 69% , patient survival at 6 months was 33% . In the test group did not occur > 2 degrees hemoptysis events.
CALGB30306 Ⅱ clinical trial in 2005,3 ~ 2006,4,72 patients with untreated extensive-stage SCLC patients according to inclusion criteria involved in the clinical trial program for the cisplatin + CPT11 + bevacizumab . The results did not occur > 2 degrees hemoptysis adverse reactions. In evaluable patients , 2 cases of CR (3%), 42例PR (59%) RR was 80% , with a median survival of 10.6 months , PFS 7 months.
Genentech reports Ⅱ clinical trials , patients were untreated into the group 's limited- SCLC, programs for the concurrent chemoradiotherapy , chemotherapy is CPT11 + carboplatin + bevacizumab . After the end of chemotherapy , maintenance therapy with bevacizumab to six months. Entry into the study group , 29 patients, 2 cases of serious adverse events occurred , that tracheoesophageal fistula , one case died as a result . The third case of gas accumulation and upper gastrointestinal bleeding, after death, but for unknown reasons. The three cases of adverse events occurred in the bevacizumab maintenance treatment period, and all patients with persistent esophagitis .
( Three ) VEGFR inhibitor
VEGFR tyrosine kinase channel plurality of small molecule inhibitors also SCLC clinical trials conducted in patients . Including sorafenib , AZD2171, Sunitinib and ZD6474 and so on.
ZD6474 in Canada, the National Cancer Research Centre (CAN-NICIL-BR20) Phase Ⅱ clinical study conducted in 107 patients with previously untreated SCLC patients after chemotherapy or radiation into the group , including 46 cases of limited stage , 61 cases for a wide range of study programs divided into two groups , namely the maintenance therapy, a group taking ZD6474, another group of placebo , the median PFS results of the two groups and no significant difference in overall survival .
AZD2171 (Cediranib) inhibit VEGFR-1, -2 and -3 tyrosine kinase phosphorylation .
2008 Ramalingam have been reported for AZD2171 Phase Ⅱ clinical trial who were enrolled after platinum-based chemotherapy after disease progression in SCLC, 13 patients solution of AZD2171, 30mgQD, 4 weeks for a period , the median treatment period of 2, the main toxicities were fatigue , diarrhea, skin rash and hypertension , efficacy evaluation without PR, 8例SD, median PFS8 weeks. Disease progression after treatment , circulating endothelial cells (CEC) count increased plasma VEGF levels increased. Therefore, further recommendations should be combined with chemotherapy treatment.
Thalidomide has been shown in experiments on SCLC with anti- angiogenesis and apoptosis. 2007 Report thalidomide Ⅱ clinical trials CWRU-1502, into the group by extensive stage SCLC, after standard chemotherapy, achieved CR or PR after , and then enter the thalidomide maintenance therapy. Median survival of 13 months (95% C1 10 ~ 16 months ) , 1 -year survival 52% (95% C1 32.5 ~ 67.9 months ) .
LLCG research report in 2007 , the Phase Ⅲ clinical trial patients are extensive stage SCLC, randomization , research programs divided into two groups , one group of VP16 + carboplatin + thalidomide , another group of VP16 + carboplatin + placebo. From 2003 to 2006, 724 cases enrolled 365 patients randomized into the containing thalidomide , 359 cases into with the placebo group , the results were similar overall survival time , 2-year survival rates were 13%. The median survival was 10.2 months and 10.5 months (P0.24), PFS no difference. In the thalidomide group of major adverse events pulmonary embolism anddeep vein thrombosis ( Four ) Src tyrosine kinase inhibitor
Src family proteins from various non- receptor tyrosine kinase regulatory signals , including tumor cell surface molecules , G protein binding receptor , growth factors and adhesion factors molecules. Src family , including c-Src, Yes, Yrk, Fyn, Lyn, Hck, Lck, Fgr and BIKSrc family genes mostly in blood cells, but c-Src, Fyn and Yes in different tissues, such as epithelial cells. Lung cancer cell lines and tumor tissues by immunoblotting and immunohistochemical expression of c-Src can be displayed . SCLC, adenocarcinoma and squamous cell carcinoma are also overexpression of c-Src , but not found in normal lung tissue .
Dasatinib (BMS354825) is a tyrosine kinase phosphorylation inhibitor which can block the phosphorylation of Src kinase and phosphorylation of other kinases, including c-Src, Lck, Fyn, Yes, Abl, c-kit and EphA2. Dasatinib inhibits cell cycle , blocking the G1 → S phase , mainly through the Rb gene and P27 products dephosphorylation . CALGB30602 dasatinib clinical trials primarily used for sensitive relapsed SCLC.
AZD0530 has a pair of c-Src and c-Abl inhibition , has been carried out Ⅱ clinical trials , mainly for patients with extensive-stage SCLC after four cycles of chemotherapy .
( Five ) class of recombinant molecules
N901 is a recombinant molecule of murine anti- CD56 monoclonal antibody covalently coupled to ricin molecule , SCLC tumor cell surface CD56 epitope , which is the natural neural cell adhesion molecule , a target point of treatment N901 . Treatment with N901 SCLC, 1 patients had clinical effect , but all patients participating in the study have murine antibody and its ricin has limitations immune response. Has been modified to fully humanized antibody , and which is coupled to an new substances , the United Almond (Maytasinoid) effective molecules , called DM-1, a beauty Almond microtubule depolymerization complexes. Recombinant molecule now known BB10901 or humanized N901-DM1, Ⅱ clinical trial enrolled patients with recurrent SCLC, if their cancer cell surface CD56 expression , try BB10901, for the first time into the group of 10 patients, 2 cases of PR, currently still in progress.
( Six ) apoptotic molecules
When the adjustment is lost with SCLC apoptosis Bcl-2 expression , which means the continued survival of tumor cells , and tumor resistance to chemotherapy . In human SCLC with high expression of Bcl-2 80%. Preclinical studies have shown that antisense oligonucleotides can target Bc1-2 mRNA levels of Bcl-2 inhibition . Therefore, inhibitors of Bcl-2 has a higher potential targeting ability and high specificity . Small molecule inhibitors of Bcl-2 SCLC cell lines available on the dramatic anti- tumor effect.
Blimersen (G3139) is the Bcl-2 antisense oligonucleotides inhibit the Bcl-2 level, two clinical studies and a randomized Phase Ⅱ clinical study was conducted Oblimersen combined cytotoxic chemotherapy SCLC, can significantly enhance the standard chemotherapy .
Ⅰ clinical research program for the treatment of recurrent paclitaxel Oblimersen of SCLC, there are two cases of patients originally expected poor prognosis after treatment maintained SD, another one case the disease did not progress to keep six months, but did not observe an effective response .
The second clinical trial evaluated Oblimersen + carboplatin + VP16 extensive first-line treatment of SCLC, 12 cases 10 cases effective, efficient and 83%.
CALGB conducted a phase Ⅱ clinical trial comparing carboplatin + VP16 and carboplatin + VP16 + Oblimersen, results Oblimersen no increase in RR and survival time. Why is there such a result ? Speculate that there is no sufficiently suppressed target Bcl-2 , as measured in peripheral blood did not show Bcl-2 protein levels decrease .
Other related Bcl-2 family of targeted drugs , will soon enter clinical studies . ABT-263 is an oral agent , Bcl-2/Bcl-xL inhibitors will have to be multi-center phase Ⅰ / Ⅱ clinical study for relapsed SCLC. Obatoclax and two AT-101 is another inhibitor of Bcl-2 . Obatoclax + topotecan for relapsed SCLC studies are in progress . NCI ongoing AT-101 monotherapy for relapsed SCLC Phase Ⅱ clinical study.
( Seven ) Hedgehog (Hh) targeted therapy
Hh is the SCLC and embryonic cells ( stem cells ) an important signaling pathway , which regulates stem cells / progenitor cells in different ways , in the Mammalia class animal 's trachea and lung development plays an important role , and to promote SCLC with neuroendocrine differentiation tendencies . Smoothend (Smo) is through a membrane protein , Hh downstream signaling preaching must. When Smo inhibition , can inhibit the Hh pathway activity. Smo inhibition of Hh pathway analogs disinhibition may have a high specificity and potential anti-tumor effect, so the tumor target Smo research direction , when the SCLC patients with high expression of Sonic Hh ligand when , Smo inhibitors can inhibit SCLC. For preparations such as GDC-0449, for the oral administration. Has been carried out Ⅰ clinical safety and determine the treatment dose study . Currently upcoming Phase Ⅱ trial .
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