Table 1 Potential molecular targets and therapeutic agents linked to the DCC reawakening mechanism.
Target | Drug | Strategy | Clinical trial | Treatment | Current status | Disease | Clinical results |
|---|---|---|---|---|---|---|---|
Integrin β1 | ATN-161 | Non-RGD-based integrin-binding peptide | Phase I/II (NCT00352313) | Combinatory (with carboplatin) | Completed | Recurrent malignant glioma | All of the treatment-related adverse events were grade 2 or lower65. |
Phase II (NCT00131651) | Single | Terminated | Advanced renal cell carcinoma | Unposted | |||
Integrin α5β1 | Volociximab | Chimeric monoclonal antibody against integrin α5β1 | Phase Ib (NCT00666692, NCT00654758) | Combinatory (with carboplatin, paclitaxel, bevacizumab) | Completed | Advanced non-small-cell lung cancer (NSCLC) | Treatment was well tolerated, and dose-limiting toxicities were not observed. Approximately one-quarter of patients displayed stable disease66. |
Phase II (NCT00369395) | Single | Terminated | Metastatic melanoma | Terminated because of insufficient clinical activity | |||
Phase II (NCT00099970) | Combinatory (with dacarbazine) | Completed | Metastatic melanoma | Unposted | |||
Phase II (NCT00516841) | Single | Terminated | Platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer | Terminated based on lack of efficacy67 | |||
Phase II (NCT00401570) | Combinatory (with gemcitabine) | Completed | Metastatic pancreatic cancer | Unposted | |||
Phase II (NCT00100685) | Single | Terminated | Metastatic renal cell carcinoma | Unposted | |||
Phase I/II (NCT00635193) | Combinatory (with doxorubicin) | Completed | Ovarian cancer, primary peritoneal cancer | Unposted | |||
Integrin α2 | E7820 | Oral inhibitor of integrin alpha-2 expression (sulfonamide-based small molecule) | Phase I (NCT01773421) | Single | Completed | Advanced solid tumors | E7820 decreases integrin alpha-2 in surrogate tissues and is associated with stable disease68. |
Phase I/II (NCT01347645) | Single | Completed | Locally advanced/metastatic colon/rectal cancer | E7820 treatment was safe and tolerable in 2/3 of patients69. | |||
Phase I/II (NCT01133990) | Combinatory (with FOLIRI) | Completed | Locally advanced/metastatic colon/rectal cancer | Limited efficacy in locally advanced or metastatic colorectal carcinoma69. | |||
Phase II (NCT00309179) | Combinatory (with cetuximab) | Completed | Advanced colorectal cancer | E7820 combined with cetuximab is well tolerated. A single partial response was observed in a total of seven KRAS-mutant pateints70. | |||
Phase I (NCT00078637) | Single | Completed | Neoplasms, lymphoma, malignant cancers | Unposted | |||
Integrin αv | Intetumumab (CNTO-95) | Panintegrin αv antibody | Phase I (NCT00888043) | Combinatory (with Avastin) | Completed | Solid tumors | Unposted |
Phase II (NCT00537381) | Combinatory (with docetaxel and prednisone) | Completed | Metastatic hormone-refractory prostate cancer | Treatment resulted in shorter progression-free survival without additional toxicity71. | |||
Phase I/II (NCT00246012) | Single or combinatory (with dacarbazine) | Completed | Melanoma (stage 4) | CNTO-95 showed a favorable safety profile and nonsignificant effects on overall survival72. | |||
Integrin αv | Abituzumab | Panintegrin αv antibody | Phase I (NCT00848510) | Single | Completed | Colorectal/ovarian cancer with liver metastases | It was tolerable despite hypersensitivity reactions73. |
Phase I/II (NCT01008475) | Combinatory (with irinotecan and cetuximab) | Completed | Kras-wild-type metastatic colorectal cancer | A trend toward improved overall survival was observed74. | |||
Phase II (NCT01360840) | Single | Completed | Asymptomatic/mildly symptomatic metastatic castrate-resistant prostate cancer | Although progression-free survival was not significantly extended, abituzumab appears to have specific activity in prostate cancer-associated bone lesions75. | |||
Integrin αvβ3 | Etaratuzumab (MEDI-522) | Humanized higher-affinity variants derived from murine antibody LM609 | Phase I/II (NCT00027729) | Single | Completed | Advanced colorectal cancer | Unposted |
Phase I (NCT00049712) | Single | Completed | Refractory advanced solid tumors, lymphoma | Unposted | |||
Phase I/II (NCT00284817) | Single | Completed | Irinotecan-refractory advanced colorectal cancer | Unposted | |||
Phase II (NCT00072930) | Combinatory (with docetaxel, prednisone, zoledronic acid) | Completed | Metastatic androgen-independent prostate cancer | Unposted | |||
Phase I/II (NCT00684996) | Combinatory (with bevacizumab) | Terminated | Unresectable/metastatic kidney cancer | Posted | |||
Phase I (NCT00263783) | Single | Completed | Refractory solid tumors | Unposted | |||
Phase II (NCT00066196) | Single or combinatory (with dacarbazine) | Completed | Metastatic melanoma | MEDI-522 appears to be well tolerated. The overall survival results suggested potential clinical activity of MEDI-52276. | |||
Phase I (NCT00111696) | Single | Completed | Advanced malignant melanoma | Unposted | |||
Integrin αv | MK-0429 | An equipotent inhibitor of multiple αv integrins | Phase I (NCT00302471) | Single | Completed | Prostate cancer with metastatic bone disease | MK‐0429 was generally well tolerated and a reduction in bone turnover was observed77. |
Integrin αvβ3 and αvβ5 | Cilengitide (EMD121974) | A constrained cyclic pentapeptide based on the RGD sequence | Phase II (NCT00103337) | Single | Completed | Metastatic prostate cancer | Unposted |
Phase II (NCT00089388) | Single | Terminated (administratively complete) | Acute myeloid leukemia | Unposted | |||
Phase I (NCT00063973) | Single | Completed | Children with refractory primary brain tumors | Unposted | |||
Phase I (NCT01118676) | Combinatory (with radiochemotherapy) | Completed | Locally advanced NSCLC | Unposted | |||
Phase II (NCT00679354) | Single | Completed | Recurrent/Progressive high-grade glioma that has not responded to a standard regimen | Posted | |||
Phase I (NCT00022113) | Single | Completed | Advanced solid tumors | Dose-limiting toxicity was not observed78. | |||
Phase II (NCT00121238) | Single | Completed | Prostate cancer | Cilengitide was well tolerated but had no detectable clinical activity78. | |||
Phase II (NCT00093964) | Single | Completed | Recurrent glioblastoma multiforme | Posted | |||
Phase II (NCT01517776) | Combinatory (with temozolomide) | Terminated (due to an altered benefit/risk ratio) | Refractory high-grade gliomas, diffuse intrinsic pontine gliomas in children and adolescents | Unposted | |||
Phase I (NCT00077155) | Single | Completed | Advanced solid tumors, lymphoma | Unposted | |||
Phase I/II (NCT00006093) | Single | Completed | Progressive/recurrent glioma | No dose-limiting toxicity was observed78. | |||
uPA | WX-671 | Orally available prodrug of WX-UK1 | Phase II (NCT00499265) | Combinatory (with gemcitabine) | Completed | Locally advanced pancreatic cancer that cannot be removed by surgery | More patients achieved a partial response with WX-671 combination therapy than with standard of care79. |
Phase II (NCT00615940) | Combinatory (with Capecitabine) | Completed | Her2-negative metastatic breast cancer | Unposted | |||
WX-UK1 | A serine protease inhibitor that inhibits uPA as well as other serine proteases | Phase I (NCT00083525) | Combinatory (with capecitabine) | Completed | Advanced malignancies | Unposted | |
FAK | GSK2256098 | A tyrosine kinase inhibitor working at the autophosphorylation site (Tyr 397) of FAK | Phase I (NCT01938443) | Combinatory (with trametinib) | Completed | Advanced solid tumors | Trametinib exposure was increased in combination with GSK2256098. Clinical efficacy was limited in combinatory therapy. The safety profile was acceptable80. |
Phase I (NCT01138033) | Single | Completed | Solid tumors | GSK2256098 has an acceptable safety profile and has clinical activity in patients with mesothelioma, particularly those with merlin loss81. | |||
Phase I (NCT00996671) | Single | Completed | Healthy volunteers | Unposted | |||
Phase II (NCT02523014) | Single | Suspended (not currently open to patient registration) | Intracranial meningioma, recurrent meningioma with NF2 gene mutation | Unposted | |||
Phase II (NCT02428270) | Combinatory (with trametinib) | Active, not recruiting | Advanced pancreatic cancer | The GSK2256098 and trametinib combination was well tolerated but was not effective in patients82. | |||
VS-4718 | VS-4718 blocks fibronectin-stimulated FAK autophosphorylation at Tyr397 | Phase I (NCT02651727) | Combinatory (with paclitaxel and gemcitabine) | Terminated | Pancreatic cancer | Unposted | |
Phase I (NCT01849744) | Single | Terminated (sponsor’s decision to deprioritize the program) | Nonhematologic cancers, metastatic cancer | Unposted | |||
Phase I (NCT02215629) | Single | Withdrawn | Acute myeloid leukemia, B cell acute lymphoblastic leukemia | – | |||
VS-6063 (defatinib) | VS-6063 inhibits FAK phosphorylation at the Tyr397 | Phase I (NCT00787033) | Single | Completed | Advanced nonhematologic malignancies | VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible83. | |
Phase I (NCT01943292) | Single | Completed | Nonhematologic cancers | Posted | |||
Phase I/Ib (NCT01778803) | Combinatory (with paclitaxel) | Completed | Advanced ovarian cancer | Defactinib was generally well tolerated in combination with weekly paclitaxel84. | |||
Phase I (NCT03875820) | Combinatory (with RO5126766) | Recruiting | NSCLC, solid tumors, low-grade serous ovarian cancer, colorectal cancer | – | |||
Phase I (NCT02546531) | Combinatory (with pembrolizumab and gemcitabine) | Active, not recruiting | Advanced solid tumors, solid tumors, pancreatic cancer | – | |||
Phase I/II (NCT02758587) | Combinatory (with pembrolizumab) | Recruiting | Carcinoma, NSCLC, mesothelioma, pancreatic neoplasm | – | |||
Phase II (NCT01951690) | Single | Completed | Non-small-cell lung cancer, lung cancer | Defactinib monotherapy showed modest clinical activity in heavily pretreated patients with KRAS mutation85. | |||
Phase II (NCT02004028) | Single | Terminated (company decided to discontinue trial to focus on development program next steps) | Surgically resectable malignant pleural mesothelioma | Unposted | |||
Phase II (NCT03727880) | Combinatory (with pembrolizumab) | Recruiting | Resectable pancreatic ductal adenocarcinoma | – | |||
PKC | LXS196 | Small-molecule inhibitor for PKC | Phase I (NCT02601378) | Single or combinatory (with HDM201) | Active, not recruiting | Metastatic uveal melanoma | – |
JAK2 | Pacritinib (SB1518) | Macrocyclic pyrimidine-based JAK2 inhibitor | Phase I (NCT02342353) | Combinatory (with erlotinib) | Terminated (drug shortage) | EGFR-mutant NSCLC | Unposted |
Phase I (NCT02323607) | Combinatory (with chemotherapy) | Completed | Acute myeloid leukemia, FLT3 mutations | Unposted | |||
Phase I (NCT03601819) | Single | Recruiting | Relapsed/refractory lymphoproliferative disorders | – | |||
Phase II (NCT02277093) | Single | Terminated (FDA issued a clinical hold as pacritinib had increased side effects) | Refractory colorectal cancer | Posted | |||
Phase I/II (NCT00719836) | Single | Completed | Advanced myeloid malignancies | Pacritinib showed clinical activity in myelofibrosis with tolerable side effects86. | |||
Phase II (NCT02532010) | Combinatory (with decitabine or cytarabine) | Terminated (initially by the sponsor and later due to financial constraints) | Older patients with acute myeloid leukemia | Posted | |||
Ruxolitinib | Small-molecule inhibitor of JAK1/2 | Phase II (NCT01877005) | Single | Completed | Hodgkin’s lymphoma | Unposted | |
Phase II (NCT02876302) | Combinatory (with preoperative chemotherapy) | Recruiting | Triple-negative inflammatory breast cancer | – | |||
Phase II (NCT01423604) | Combinatory (with capecitabine) | Completed | Pancreatic cancer | Treatment was generally well tolerated and may have improved survival in patients with metastatic pancreatic cancer with evidence of systemic inflammation87. | |||
Phase II (NCT01594216) | Combinatory (with exemestane) | Completed | Estrogen receptor-positive breast cancer | Unposted | |||
Phase I/II (NCT02066532) | Combinatory (with trastuzumab) | Active, not recruiting | Metastatic HER2-positive breast cancer | – | |||
Phase I/II (NCT02041429) | Combinatory (with preoperative chemotherapy) | Active, not recruiting | Triple-negative inflammatory breast cancer | – | |||
Phase II (NCT03153982) | Single | Recruiting | Operable head and neck cancer | – | |||
Phase II (NCT00674479) | Single | Completed | Advanced hematologic malignancies | Posted | |||
Phase I/II (NCT02155465) | Combinatory (with erlotinib) | Completed | EGFR-mutant lung adenocarcinoma with acquired resistance to erlotinib | Posted | |||
Phase I (NCT01702064) | Combinatory (with nilotinib) | Completed | Chronic myeloid leukemia | The combinatory treatment was safe and tolerable, and the molecular responses were encouraging88. | |||
Phase I/II (NCT01751425) | Combinatory (with tyrosine kinase inhibitors) | Active, not recruiting | Chronic myeloid leukemia with minimal residual disease while on therapy with tyrosine kinase inhibitors | The combinatory treatment was safe and tolerable. There was no apparent clinical benefit89. | |||
AZD1480 | ATP-competitive inhibitor of JAK1 and 2 kinases | Phase I (NCT01219543) | Single | Terminated (compound development discontinued) | Solid tumors, advanced solid malignancies, advanced hepatocellular carcinoma, EGFR- and/or ROS-mutant non-small-cell lung cancer, lung carcinoma metastasis, gastric cancer | Unposted | |
Phase I (NCT01112397) | Single | Terminated (decision to stop development of AZD1480) | Solid tumors | Unposted | |||
STAT3 | WP1066 | Dephosphorylation and nuclear export of constitutively phosphorylated STAT3 | Phase I (NCT01904123) | Single | Recruiting | Recurrent malignant glioma, progressive metastatic melanoma in the brain | – |
AZD9150 | STAT3 antisense oligonucleotide | Phase I (NCT03527147) | Combinatory (with acalabrutinib) | Recruiting | Relapsed/refractory aggressive non-Hodgkin’s lymphoma | – | |
Phase I/II (NCT03421353) | Combinatory (with durvalumab or chemotherapy) | Active, not recruiting | Advanced solid tumors | – | |||
Phase I/Ib (NCT01839604) | Single | Completed | Advanced/metastatic hepatocellular carcinoma | Posted | |||
Phase I/II (NCT01563302) | Single | Completed | Advanced cancers | AZD9150 was well tolerated and showed efficacy in a subset of heavily pretreated patients with diffuse large B cell lymphoma90. | |||
OPB-51602 | A small-molecule SH2 domain-targeting STAT3 inhibitor | Phase I (NCT02058017) | Single | Terminated (because of unbearable lactic and metabolic acidosis) | Locally advanced nasopharyngeal carcinoma | Unposted | |
Phase I (NCT01423903) | Single | Completed | Advanced cancer | Unposted | |||
Phase I (NCT01344876) | Single | Completed | Hematologic malignancies | OPB-51602 was safe and well tolerated. However, long-term administration at higher doses was difficult with the daily dosing schedule, and no response was seen91. | |||
Phase I (NCT01184807) | Single | Completed | Advanced solid tumors | OPB-51602 demonstrated promising antitumor activity, particularly in NSCLC. Less frequent dosing should be explored92. | |||
COX1/2 | Sulindac | Nonsteroidal anti-inflammatory drug (NSAID), arylalkanoic acid derivative | Phase III (NCT00118365) | Combinatory (with eflornithine) | Completed | Preventing colorectal cancer with colon polyps | Posted |
Phase III (NCT01349881) | Single and combinatory (with eflornithine) | Recruiting | Reducing the three-year event rate of adenomas and second primary colorectal cancers in patients previously treated for stages 0 through III colon/rectal cancer | – | |||
Phase I (NCT00245024) | Single | Completed | Preventing breast cancer in women at high risk of breast cancer | Unposted | |||
Phase II (NCT01856322) | Single | Terminated (due to lack of accrual) | Advanced colorectal cancer | – | |||
Phase II (NCT00039520) | Combinatory (with docetaxel) | Completed | Metastatic/recurrent breast cancer | Unposted | |||
Phase II (NCT00368927) | Single | Completed | Preventing lung cancer in current/former smokers with bronchial dysplasia | Sufficient benefits were not observed93. | |||
Celecoxib | a COX-2-selective NSAID | Phase II (NCT01695226.) | Single | Completed | Preoperative celecoxib treatment in breast cancer | Celecoxib induced transcriptional programs supporting antitumor activity94. | |
Phase III (NCT 01041781) | Combinatory (with gemcitabine, pemetrexed disodium and carboplatin) | Terminated (recommended by the Data and Safety Monitoring Board) | Advanced NSCLC | A urinary metabolite of prostaglandin E2 was able to identify patients who could benefit from COX2 inhibition95. | |||
Phase III (NCT 02429427) | Single | Completed | Primary breast cancer | Clinical benefit was not observed. Further studies focusing on the ER + subpopulation are ongoing96,97. |
