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NKX3.1 patient samples. Taken together, these findings
suggest that patients with low NKX3.1 expression are more
likely to benefit from 5-ARI intervention, and further suggest
that these treatment-response MRs can be used as a readout
to assess the efficacy of such treatment.
4. Discussion
The rise in diagnoses of low-risk, early-stage PCa has led to a
surge in active surveillance monitoring in lieu of more
invasive procedures. Indeed, since PCa is characteristically
indolent, simply delaying progression may be highly
advantageous for many patients. In this context, 5-ARIs
have been investigated as an adjunct to active surveillance
; however, considering their potential adverse side
effects and variable response, it would be valuable to
identify the subset(s) of patients who are most likely to
benefit from 5-ARI intervention.
Using co-clinical analyses of GEMMs and human PCa to
investigate the phenotypic and molecular contexts in which
5-ARIs may be most effective, we found that prostate
tumors with low NKX3.1 expression are more likely to
respond to and benefit from 5-ARI treatment. NKX3.1 is a
prostate-specific homeobox gene that is essential for proper
prostate development, differentiation, specification, and
stem cell function ; conversely, loss of
NKX3.1 function leads to defects in prostate differentiation,
as well as preinvasive prostate phenotypes that share
molecular conservation with early-stage human PCa
. Notably, NKX3.1 is localized to chromosomal
region 8p21, which undergoes deletion in a majority (>60%)
of PCas at early stages, while NKX3.1 expression is reduced
in cancer progression and coincident with cancer initiation
. Thus, given the biological functions of NKX3.1,
combined with the prevalence and significance of its loss of
expression in early-stage PCa, a substantial number of men
may benefit from assessment of NKX3.1 expression as a way
of selecting for 5-ARI intervention. However, this will need
to be tested in prospective clinical trials in which patients
on active surveillance are evaluated to determine whether
NKX3.1 expression correlates with response to 5-ARI
intervention and whether such intervention delays pro-
gression. We further propose that the efficacy of 5-ARI
intervention can be monitored using the MR signature of
treatment response identified here.
Our study also highlights the importance of incorporat-
ing precision medicine for cancer prevention; precision
medicine has been widely adopted, albeit primarily for
cancer therapeutics . In particular, our findings suggest
that the varied response to 5-ARIs among PCa patients on
active surveillance may reflect differences in levels of
NKX3.1 expression, which can be readily evaluated at the
mRNA or protein level. Moreover, the co-clinical paradigm,
with the aim of integrating analyses of GEMMs and human
clinical studies to provide information on patient care ,
has largely been limited to therapeutic studies until now.
Our study highlights the importance of using a co-clinical
approach for cancer prevention. We envision that future
studies investigating the long-term benefit of 5-ARIs for
patients on active surveillance, and more generally other
interventions, can be guided by co-clinical studies in a
precision prevention paradigm .
5. Conclusions
Our results suggest that patients with low NKX3.1 expres-
sion are likely to benefit from intervention with 5-ARIs, and
that the beneficial consequences can be evaluated using a
molecular signature of treatment response.
Author contributions: Cory Abate-Shen had full access to all the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Dutta, Mitrofanova, Abate-Shen.
Acquisition of data: Dutta, Panja, Virk, Kim, Zott, Cremers, Golombos, Liu,
Mosquera.
Analysis and interpretation of data: Dutta, Panja, Virk, Zott, Cremers,
Mosquera, Barbieri, Mitrofanova, Abate-Shen.
Drafting of the manuscript: Dutta, Mitrofanova, Abate-Shen.
Critical revision of the manuscript for important intellectual content:
Golombos, Mosquera, Mostaghel, Barbieri.
Statistical analysis: Dutta, Golombos, Mosquera, Mitrofanova.
Obtaining funding: Dutta, Mostaghel, Barbieri, Mitrofanova, Abate-Shen.
Administrative, technical, or material support: Mostaghel.
Supervision: Barbieri, Mitrofanova, Abate-Shen.
Other: None.
Financial disclosures: Cory Abate-Shen certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: Aditya Dutta was supported in
part by the National Center for Advancing Translational Sciences, National
Institutes of Health, grant UL1 TR000040. Christopher E. Barbieri received
funding from the National Cancer Institute (K08CA187417-01), the
Prostate Cancer Foundation, a Urology Care Foundation Rising Star in
Urology Research Award, and a Damon Runyon Cancer Research
Foundation MetLife Foundation Family Clinical Investigator award. Elahe
A. Mostaghel was supported in part by Pacific Northwest Prostate Cancer
SPORE grant P50 CA097186. Antonina Mitrofanova is a recipient of a
Prostate Cancer Foundation Young Investigator Award. Cory Abate-Shen
had access to the HICCC facilities supported by the Cancer Center Support
Grant (P30 CA013696-40) and the National Center for Advancing
Translational Sciences (UL1TR001873), and received support from the
National Cancer Institute (U01 CA141535-05 and P01 CA154293-03) and
an American Cancer Society Research Professorship supported in part by a
generous gift from the F.M. Kirby Foundation. The sponsors [18_TD$DIFF]did not play a
role in manuscript approval.
Acknowledgments: We are grateful to Edward Gelmann M.D. for helping
to obtain the patient cohorts for this study and for helpful discussions.
Immunohistochemistry was performed at the Translational Research
Program, Department of Pathology and Laboratory Medicine at Weill
Cornell Medicine. RNA sequencing was carried out at the J.P.
Sulzberger Columbia Genome Center at Columbia University Medical
Center (mouse data) and the Genomics core facility at Weill Cornell
Medicine (human data). Antonina Mitrofanova acknowledges access to
the HPC facilities and support of the computational biology scientists
of the Office of Advanced Research Computing (OARC) at Rutgers
University.
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