14 Perspectives of Aptamers for Medical Applications
423
advanced renal clear carcinoma (RCC) always died within 24 months. In a phase I
study in patients with RCC [103], AS1411 produced one complete response (CR) and
one partial response (PR) among twelve patients with metastatic RCC. Rosenberg and
co-worker [104] led an open-label, single-arm, multi-center, phase II study to investigate the efficacy and safety of the DNA aptamer AS1411 in the treatment of patients
with advanced RCC who had failed tyrosine kinase inhibitor therapy. The patient
achieved a partial response in this study shows a dramatic shrinkage to 84% decrease
in diameters of target tumor lesions accompany with a longer partial response period
over 24 months. Although this trial has a low level of activity because of unselected
patients without overexpressing nucleolin in metastatic RCC, the nucleolin pathway
may still represent a suitable target for the tumor overexpressing nucleolin.
NOX-A12, also known as olaptesed pegol, is a promising aptamer that has already
entered the clinical trials in target therapy for tumors. This RNA aptamer can bind and
neutralize chemokine CXCL12, thus interfere the process of tumor cell migration.
NOX-12 was demonstrated to be safe in clinical phase I study [105], it has completed
a phase 2 clinical trial in patient with relapsed chronic lymphocytic leukemia. NOXA12 presents a pretty well pharmacodynamics effects with 86% response rates after
treatment. It also shows a lower toxicity when combining with other chemical drugs
[106].
Targeting EGFR is another effective strategy in cancer treatment. For instance,
triple-negative breast cancers (TNBCs) [107] are defined by tumors that lack estrogen
receptor, progesterone receptor, and human epidermal growth factor receptor 2
(HER2) overexpression. TNBCs constitute an important clinical challenge, as they do
not respond to endocrine treatment and other targeted therapies. Camorani et al. [108]
generated a nuclease-resistant RNA aptamer, named CL4. CL4 effectively binds to
the extracellular domain IV of human EGFR to inhibit the receptor in some kinds of
tumor such as non-small cell lung carcinoma, glioblastoma, and breast cancer. CL4
aptamer enables the inhibition of EGFR-integrin αvβ3 interaction, VM, and tumor
growth in a xenograft TNBC model [108]. This aptamer can also specifically deliver
therapeutic small interfering RNAs (siRNAs) to orthotopic TNBC nude mice [109,
110]. All the results indicate that CL4 has the possibility to be used as a therapeutic
tool in EGFR-positive TNBCs.
EGFR can also combine with other molecules to form dimerization to enhance
the effects on target therapy. For example, HER2 [111] is normally overexpressed
in cancer-like breast, ovary, stomach, prostate, lung, colon, and head and neck.
Inhibiting EGFR and HER2 have shown remarkably higher antitumor activity than
the administration of single agents, Xue et al. [111] constructed a HER2 aptamer
with EGFR siRNA sense strand,named HEH. In vitro study showed HEH can effectively be taken up into HER2-expressing cells, silence EGFR gene, and reduce HER2
expression. HEH can also trigger apoptosis by inhibiting the expression of EGFR and
HER2 in breast cancer xenograft models. This study demonstrated that HEH has great
potential as a new HER2 targeted drug to provide a cure for many HER2-positive
cancers.
Yu et al. [112] constructed a chimera by fusing a single EGFR siRNA between the
HER2 and HER3 aptamers to target EGFR/HER2/HER3 in one molecule (H2EH3).
423
advanced renal clear carcinoma (RCC) always died within 24 months. In a phase I
study in patients with RCC [103], AS1411 produced one complete response (CR) and
one partial response (PR) among twelve patients with metastatic RCC. Rosenberg and
co-worker [104] led an open-label, single-arm, multi-center, phase II study to investigate the efficacy and safety of the DNA aptamer AS1411 in the treatment of patients
with advanced RCC who had failed tyrosine kinase inhibitor therapy. The patient
achieved a partial response in this study shows a dramatic shrinkage to 84% decrease
in diameters of target tumor lesions accompany with a longer partial response period
over 24 months. Although this trial has a low level of activity because of unselected
patients without overexpressing nucleolin in metastatic RCC, the nucleolin pathway
may still represent a suitable target for the tumor overexpressing nucleolin.
NOX-A12, also known as olaptesed pegol, is a promising aptamer that has already
entered the clinical trials in target therapy for tumors. This RNA aptamer can bind and
neutralize chemokine CXCL12, thus interfere the process of tumor cell migration.
NOX-12 was demonstrated to be safe in clinical phase I study [105], it has completed
a phase 2 clinical trial in patient with relapsed chronic lymphocytic leukemia. NOXA12 presents a pretty well pharmacodynamics effects with 86% response rates after
treatment. It also shows a lower toxicity when combining with other chemical drugs
[106].
Targeting EGFR is another effective strategy in cancer treatment. For instance,
triple-negative breast cancers (TNBCs) [107] are defined by tumors that lack estrogen
receptor, progesterone receptor, and human epidermal growth factor receptor 2
(HER2) overexpression. TNBCs constitute an important clinical challenge, as they do
not respond to endocrine treatment and other targeted therapies. Camorani et al. [108]
generated a nuclease-resistant RNA aptamer, named CL4. CL4 effectively binds to
the extracellular domain IV of human EGFR to inhibit the receptor in some kinds of
tumor such as non-small cell lung carcinoma, glioblastoma, and breast cancer. CL4
aptamer enables the inhibition of EGFR-integrin αvβ3 interaction, VM, and tumor
growth in a xenograft TNBC model [108]. This aptamer can also specifically deliver
therapeutic small interfering RNAs (siRNAs) to orthotopic TNBC nude mice [109,
110]. All the results indicate that CL4 has the possibility to be used as a therapeutic
tool in EGFR-positive TNBCs.
EGFR can also combine with other molecules to form dimerization to enhance
the effects on target therapy. For example, HER2 [111] is normally overexpressed
in cancer-like breast, ovary, stomach, prostate, lung, colon, and head and neck.
Inhibiting EGFR and HER2 have shown remarkably higher antitumor activity than
the administration of single agents, Xue et al. [111] constructed a HER2 aptamer
with EGFR siRNA sense strand,named HEH. In vitro study showed HEH can effectively be taken up into HER2-expressing cells, silence EGFR gene, and reduce HER2
expression. HEH can also trigger apoptosis by inhibiting the expression of EGFR and
HER2 in breast cancer xenograft models. This study demonstrated that HEH has great
potential as a new HER2 targeted drug to provide a cure for many HER2-positive
cancers.
Yu et al. [112] constructed a chimera by fusing a single EGFR siRNA between the
HER2 and HER3 aptamers to target EGFR/HER2/HER3 in one molecule (H2EH3).