TY - JOUR
T1 - Targeting nodal in conjunction with dacarbazine induces synergistic anticancer effects in metastatic melanoma
AU - Hardy, Katharine M.
AU - Strizzi, Luigi
AU - Margaryan, Naira V.
AU - Gupta, Kanika
AU - Murphy, George F.
AU - Scolyer, Richard A.
AU - Hendrix, Mary J.C.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. Despite a complete response in fewer than 5% of patients, the chemotherapeutic agent dacarbazine (DTIC) remains the reference drug after almost 40 years. More recently, FDAapproved drugs have shown promise but patient outcome remains modest, predominantly due to drug resistance. As such, combinatorial targeting has received increased attention, and will advance with the identification of new molecular targets. One attractive target for improvingmelanomatherapy is the growth factor Nodal, whose normal expression is largely restricted to embryonic development, but is reactivated in metastatic melanoma. In this study, we sought to determine how Nodal-positive human melanoma cells respond to DTIC treatment and to ascertain whether targeting Nodal in combination with DTIC would be more effective than monotherapy. A single treatment with DTIC inhibited cell growth but did not induce apoptosis. Rather than reducing Nodal expression, DTIC increased the size of the Nodal-positive subpopulation, an observation coincident with increased cellular invasion. Importantly, clinical tissue specimens from patients with melanomas refractory to DTIC therapy stained positive for Nodal expression, both in pre-and post-DTIC tumors, underscoring the value of targeting Nodal. In vitro, anti-Nodal antibodies alone had some adverse effects on proliferation and apoptosis, but combining DTIC treatment with anti-Nodal antibodies decreased cell growth and increased apoptosis synergistically, at concentrations incapable of producing meaningful effects as monotherapy.
AB - Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. Despite a complete response in fewer than 5% of patients, the chemotherapeutic agent dacarbazine (DTIC) remains the reference drug after almost 40 years. More recently, FDAapproved drugs have shown promise but patient outcome remains modest, predominantly due to drug resistance. As such, combinatorial targeting has received increased attention, and will advance with the identification of new molecular targets. One attractive target for improvingmelanomatherapy is the growth factor Nodal, whose normal expression is largely restricted to embryonic development, but is reactivated in metastatic melanoma. In this study, we sought to determine how Nodal-positive human melanoma cells respond to DTIC treatment and to ascertain whether targeting Nodal in combination with DTIC would be more effective than monotherapy. A single treatment with DTIC inhibited cell growth but did not induce apoptosis. Rather than reducing Nodal expression, DTIC increased the size of the Nodal-positive subpopulation, an observation coincident with increased cellular invasion. Importantly, clinical tissue specimens from patients with melanomas refractory to DTIC therapy stained positive for Nodal expression, both in pre-and post-DTIC tumors, underscoring the value of targeting Nodal. In vitro, anti-Nodal antibodies alone had some adverse effects on proliferation and apoptosis, but combining DTIC treatment with anti-Nodal antibodies decreased cell growth and increased apoptosis synergistically, at concentrations incapable of producing meaningful effects as monotherapy.
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U2 - 10.1158/1541-7786.MCR-14-0077
DO - 10.1158/1541-7786.MCR-14-0077
M3 - Article
C2 - 25767211
AN - SCOPUS:84928042291
VL - 13
SP - 670
EP - 680
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1541-7786
IS - 4
ER -