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Robinson et al. J Cancer Metastasis Treat 2019;5:39 I http://dx.doi.org/10.20517/2394-4722.2019.15 Page 5 of 9

TELOMERE-DIRECTED THERAPIES FOR METASTATIC BREAST CANCER: CURRENT AND
FUTURE PERSPECTIVES
The functions of telomerase in tumorigenesis have been rigorously interrogated over the last several decades,
as has the potential to target telomerase therapeutically [65,81] . The telomerase inhibitors BIBR1532 and
GRN163L (also known as Imetelstat) display high efficacy in depleting the CSC pool and disrupting breast
cancer metastasis [82-85] . Indeed, Imetelstat was assessed in a Phase I clinical trial for recurrent or metastatic
breast cancer, although the trial was suspended due to dose-limiting toxicity . In addition to such toxicity
[81]
concerns, the success of telomerase inhibitors in clinical trials has thus far been moderated by the inherent
complexity of telomere homeostasis. First, telomere shortening-induced senescence can be bypassed in
[86]
the absence of functional p53 or other components of the DDR machinery . Second, the critically short
telomeres and chromosomal instability associated with telomere crisis are disproportionately associated with
metastasis [87,88] . Thus, the evolution of DTCs that underlie metastatic disease may be enhanced unwittingly
by therapies that promote telomere shortening. Despite these challenges, telomerase remains an appealing
therapeutic objective in need of innovative targeting approaches in which these evolutionary considerations
are taken into account.

Emerging telomerase-targeting strategies include cytotoxic small molecules that act as substrates for
telomerase as well as anti-telomerase immunotherapies [89-92] . Current immunotherapeutic platforms are
primarily centered on telomerase peptide or dendritic cell vaccines, which can be engineered to elicit either
CD4+ or CD8+ T cell antitumor responses . These strategies are being assessed in diverse preclinical
[93]
settings, including breast cancer. Indeed, the telomerase peptide vaccine Vx-001 is progressing through
[90]
clinical trials for advanced solid tumors . More recent investigations have examined the feasibility of
adoptive transfer of anti-telomerase chimeric antigen receptor (CAR) T cells for treating triple-negative
breast cancer . Future studies into the generalizability of anti-telomerase CAR T cell therapy to other
[94]
breast cancer subtypes, as well as the efficacy of these diverse immunotherapeutic approaches in clinical
settings will be of tremendous value.

Although the functions of specific ALT-associated proteins have been elucidated, their utility as therapeutic
targets for ALT-driven cancers has only recently been investigated. For example, the DNA damage-
responsive kinase ataxia-telangectasia and Rad3-related (ATR) is activated secondary to depletion of
ATRX, which leads to persistent retention of replication protein A (RPA) at telomeres and generation of
[95]
a recombinogenic substrate. Inhibition of ATR, in turn, triggers apoptosis of ALT-positive cells . BLM,
a RecQ DNA helicase, unwinds telomeric G-quadruplex structures and coordinates 5'→3' end resection
during telomere recombination [96,97] . Accordingly, a recently-developed small molecule inhibitor of BLM
may possess great potential as an anticancer agent against ALT-driven tumors . Finally, topoisomerase
[98]
IIIα (Topo IIIα) associates with BLM and regulates the topology of telomeric recombination intermediates.
Interestingly, genetic inactivation of Topo IIIα selectively reduces the survival of ALT-positive compared
[99]
to telomerase-positive cells . Moreover, telomerase activity is enhanced in the surviving fraction of Topo
IIIα-deficient cells , suggesting that telomerase activation provides a pathway for chemoresistance. Thus,
[100]
targeting TMMs may best be achieved using a multidrug regimen consisting of multiple anti-TMM agents
or an anti-TMM agent in combination with chemotherapy or other targeted agents . The effectiveness of
[101]
these therapeutic modalities in eliminating breast CSCs and in treating metastatic breast cancers remain
intriguing and important open questions.

CONCLUSION
By overseeing multiple pathways that promote breast cancer stemness, EMT, and metastasis, telomeres
function as critical nodes in the nexus between cellular immortalization, tumor evolution, and disease
progression. The selection of TMM likely exhibits a high degree of plasticity in different tumor cell types