Lung-MAP (SWOG S1400) is a master platform trial assessing targeted therapies in squamous NSCLC. The objective of study C (S1400C) was to evaluate the response rate to palbociclib, a cyclin-dependent ...kinase 4 and cyclin-dependent kinase 6 inhibitor, in patients with cell cycle gene abnormalities.
Patients with squamous NSCLC, a performance status of 0 to 2, and normal organ function who had progressed after at least one prior platinum-based chemotherapy with cyclin-dependent kinase 4 gene (CDK4) or cyclin D1 gene (CCND1), cyclin D2 gene (CCND2), or cyclin D3 gene (CCND3) amplifications on tumor specimens were eligible. The study was originally designed as a phase II/III trial comparing palbociclib with docetaxel, but it was modified to a single-arm phase II trial with the primary end point of response when immunotherapy was approved. If two or fewer responses were seen in the first 20 patients, then the study would cease enrollment.
A total of 88 patients (9% of patients screened) were assigned to S1400C, and 53 patients enrolled (including 17 to receive docetaxel). One patient who had been registered to receive docetaxel was re-registered to receive palbociclib after progression while taking docetaxel. The frequencies of cell cycle gene alterations in the eligible patients taking palbociclib (n = 32) were as follows: CCND1, 81% (n = 26); CCND2, 9% (n = 3); CCND3, 6% (n = 2); and CDK4, 3% (n = 1). In all, 32 eligible patients received palbociclib. There were two partial responses (response rate 6% 95% confidence interval (CI): 0%–15%), both with CCND1 amplification. Twelve patients had stable disease (38% 95% CI: 21%–54%). The median progression-free survival was 1.7 months (95% CI: 1.6–2.9 months) and the median overall survival was 7.1 months (95% CI: 4.2–12.5).
Palbociclib as monotherapy failed to demonstrate the prespecified criteria for advancement to phase III testing.
Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought ...to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting.
Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments.
In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 95% CI, 30.5 to 35.4 months for enzalutamide
34.2 95% CI, 31.4 to 37.3 months for enzalutamide and AAP; hazard ratio HR, 0.89; one-sided
= .03; boundary nominal significance level = .02). rPFS was longer in the combination arm (median rPFS, 21.3 95% CI, 19.4 to 22.9 months for enzalutamide
24.3 95% CI, 22.3 to 26.7 months for enzalutamide and AAP; HR, 0.86; two-sided
= .02). However, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone.
The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.
In recent years, the incidence of cutaneous melanoma has increased more than that of any other cancer. Dacarbazine is considered the gold standard for treatment, having a response rate of 15% to 20%, ...but most responses are not sustained. Previously, we have shown that short exposure of primary cutaneous melanoma cells to dacarbazine resulted in the upregulation of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The purpose of the present study was to determine how long-term exposure of melanoma cells to dacarbazine would affect their tumorigenic and metastatic potential in vivo.
The primary cutaneous melanoma cell lines SB2 and MeWo were repeatedly exposed in vitro to increasing concentrations of dacarbazine, and dacarbazine-resistant cell lines SB2-D and MeWo-D were selected and examined for their ability to grow and metastasize in nude mice.
The dacarbazine-resistant cell lines SB2-D and MeWo-D exhibited increased tumor growth and metastatic behavior in vivo. This increase could be explained by the activation of RAF, MEK, and ERK, which led to the upregulation of IL-8 and VEGF. More IL-8, VEGF, matrix metalloproteinase-2 (MMP-2), and microvessel density (CD-31) were found in tumors produced by SB2-D and MeWo-D in vivo than in those produced by their parental counterparts. No mutations were observed in BRAF.
Our results have significant clinical implications. Treatment of melanoma patients with dacarbazine could select for a more aggressive melanoma phenotype. We propose that combination treatment with anti-VEGF/IL-8 or MEK inhibitors may potentiate the therapeutic effects of dacarbazine.
Cellular adhesion molecules of the cadherin, integrin, and immunoglobulin superfamilies are important to both growth and metastasis of many cancers, including malignant melanoma. Malignant melanoma ...is an excellent model for studying these molecules, due in part to a sequential series of five defineable stages. As the malignant phenotype of melanoma cells changes from the noninvasive radial growth phase to the vertical growth phase, which has high metastatic potential, so does the repertoire of the cellular adhesion molecules expressed on the cells surface. The cellular adhesion molecule MCAM/ MUC18 confers metastatic potential and increased tumorgenicity to melanoma cells. MCAM/MUC18 mediates homotypic and heterotypic adhesion between melanoma cells and endothelial cells, respectively. Both types of interaction may promote metastasis at different stages in the metastasis cascade. We developed a fully humanized antibody to MCAM/MUC18 (ABX-MA1) that blocked melanoma metastasis in vivo. Furthermore, ABX-MA1 blocked the homotypic interaction between melanoma cells and endothelial cells as well as the promoter and collagenase activity of MMP-2. During melanoma progression the loss of E-cadherin expression disrupts normal homeostasis in the skin by freeing melanoma cells from structural and functional regulation by keratinocytes. The loss of functional E-cadherin is paralled by a gain in N-cadherin function that mediates homotypic interaction between melanoma cells, facilitates gap-junctional formation with fibroblasts and endothelial cells and promotes melanoma cell migration and survival. In addition, loss of E-cadherin may affect the β-catenin/wnt signaling pathways, resulting in deregulation of genes involved in growth and metastasis. The integrin family member avb3 is widely expressed on melanoma cells in the vertical growth phase. When avb3 is expressed in melanoma cells in the radial growth phase, this integrin is associated with increased tumor growth in vivo. avb3 may also promote melanoma invasion, through an interaction with MMP-2, and transendothelial migration, via a heterotypic melanoma-endothelial cell interaction. This review summarizes recent knowledge on how changes in these adhesion molecules contribute to the acquisition of the metastatic phenotype in human melanoma.
Key Words:
Melanoma, Neoplasm metastasis, Cell adhesion molecules, Extracellular matrix
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Background: Androgen receptor (AR) signaling is an important growth mechanism in mCRPC, providing the rationale for treatment with AR axis inhibitors such as ENZ and AAP. Targeting ...AR with anti-androgens such as ENZ can result in compensatory autocrine and paracrine androgenic stimulation. Therefore, using ENZ with the androgen biosynthesis inhibitor AAP to dampen these resistance mechanisms could improve clinical outcomes relative to ENZ alone. Methods: Men with progressive mCRPC by Prostate Cancer Working Group 2 criteria were eligible. Prior treatment with taxanes for mCRPC and any prior treatment with ENZ or AAP was exclusionary. Patients (pts) were randomized 1:1 to ENZ or ENZ/AAP at standard FDA-approved doses. Randomization was stratified by prior chemotherapy and Halabi prognostic three risk groups. Castrating therapy was maintained. The primary endpoint was overall survival (OS) defined as the date of randomization from date of death or last follow-up. The log-rank test had 90% power to detect a hazard ratio for OS of 0.77 with a one-sided type I error rate of 0.025. Secondary endpoints included radiographic progression free survival (rPFS) and on-treatment PSA declines. Exploratory endpoints included imaging changes, and changes in serum biomarkers such as androgens, angiokines, and circulating microRNA and RNA. The primary analysis was based on the stratified log-rank test adjusting on the stratification factors. Results: Between January 2014 and August 2016, 1311 men were randomized: 657 to ENZ and 654 to ENZ/AAP. Groups were well balanced between arms, including stratification variables. 15.6% of pts were high risk, 35.3% intermediate, and 48.1% low. Median OS was 33.6 mo (95% CI 30.5-36.4) and 32.7 mo (29.9-35.4) respectively, two-sided p = 0.53. Fifty percent PSA decline rate was 80% vs. 76.5%. Grade 3-5 adverse events (AE) (all attributions) were 55.6% and 68.8% respectively. Treatment discontinuation due to AEs occurred in 5% and 12%, pt withdrawal in 5% and 13%, and progression or death in 57% and 48% of pts respectively. Conclusions: Addition of abiraterone acetate to enzalutamide did not prolong survival in men with mCRPC. The combination resulted in more AEs than enzalutamide alone. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01949337.
Purpose : Osteosarcoma is an aggressive primary bone cancer characterized by expression of platelet-derived growth factor (PDGF) and
its cognate receptor. Coexpression of the growth factor and ...receptor suggests their role in autocrine or paracrine growth
mechanisms. It has been reported previously that STI571 has specific activity in inhibiting select tyrosine kinase receptors,
including PDGF and c-Kit. Osteosarcomas express low levels of c-Kit but abundant levels of PDGF receptor (PDGFR).
Experimental Design : To investigate the potential of STI571 as therapy for osteosarcoma, we studied its effects on PDGF-mediated cell growth
in vitro and in an in vivo mouse model.
Results : PDGF acted as a potent mitogen in a dose-dependent manner in two osteosarcoma cell lines. STI571 (1.0 μ m ) inhibited both PDGFR-α and PDGFR-β phosphorylation and the downstream phosphorylation targets extracellular signal-regulated
kinase and Akt. STI571 also inhibited PDGF-mediated growth and induced apoptosis in vitro as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase-mediated
nick end labeling staining. To study the effect of STI571 alone or in combination with Taxol in an in vivo model, an osteosarcoma cell line (KRIB) was transplanted into the tibia of athymic nude mice. Mice were treated with STI571
(50 mg/kg p.o. q M-F), Taxol (8 mg/kg i.p. weekly), or STI571 plus Taxol for 6 weeks. There was no significant difference
in tumor size between treatment and control mice. Aberrant signaling pathways downstream of the PDGFR in the v-Ki- ras oncogene-transformed KRIB cell line may in part explain this finding.
Conclusions : Our data demonstrate that STI571 inhibits PDGF-mediated growth and leads to apoptosis of osteosarcoma cells in vitro by selective inhibition of the PDGFR tyrosine kinase. The effectiveness of STI571 in our studies suggests targeting of PDGFRs
as a novel treatment for osteosarcoma.
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Background: National Comprehensive Cancer Network (NCCN) guidelines strongly recommend biomarker testing for patients with advanced non-small cell lung cancer (NSCLC), specifically with broad, ...panel-based sequencing via NGS. Our study characterized how clinicians utilized NGS testing to make first line treatment decisions in patients with stage IV NSCLC. Methods: We conducted a cross-sectional study of members within an integrated healthcare system (Kaiser Permanente Southern California) diagnosed with stage IV NSCLC who completed NGS testing (Strata Oncology) between May 2019 to June 2021. Treatment start dates were used to divide patients into those who started treatment before and after NGS results, and those who did not receive treatment after NGS results. Patients harboring alterations in seven genes (EGFR, ALK, ROS-1, BRAF, KRAS, RET, and MET) were considered candidates for targeted first line therapy. Results: A sample of 760 patients with stage IV NSCLC completed NGS testing. The mean time from NGS order to result was 25 days. Of the 760 in the sample, 284 (37%) and 262 (34%) initiated treatment before and after NGS results were reported, respectively, while the remaining 214 (28%) did not receive any treatment up to 120 days after the NGS results were reported. 43% (323/760) of the sample was found to have a targetable mutation on NGS, of whom only 38% (124/323) initiated first line treatment with a targeted therapy. 56/124 (45%) were treated with targeted therapy prior to NGS results and 68/124 (55%) were treated with targeted therapy after NGS results. 61% (118/193) of EGFR, ALK, or ROS mutated patients started targeted therapy. 67/323 with a driver mutation did not receive any treatment and were referred to hospice. For those patients who initiated targeted therapy prior to NGS results, it suggests that clinicians ordered single gene testing in parallel with NGS, and that these results were available prior to NGS. Conclusions: NGS tests results were not exclusively used to inform first line treatment decisions in most patients with stage IV NSCLC, as most patients found to have a targetable mutation, were not treated with targeted therapy. Possible explanations include lengthy turnaround times for NGS testing and the availability of more timely single gene testing.
Purpose: The activator protein (AP)-2α transcription factor plays a crucial role in the progression of several human tumors, including
malignant melanoma, prostate, and breast cancer. Loss of AP-2α ...results in deregulation of several genes with AP-2α binding
motifs such as E-cadherin , p21 WAF1 , MMP-2 , MCAM/MUC18 , VEGF , and c-KIT . The purpose of our study was to determine AP-2α expression distribution among grades of gliomas and any possible effect
on prognosis.
Experimental Design: A tissue microarray was assembled from all surgical glioma cases with available tissue samples at M.D. Anderson Cancer Center
since 1986 to include 72 glioblastomas, 49 anaplastic astrocytomas, 9 low-grade astrocytoma, 37 oligodendrogliomas, 37 anaplastic
oligodendrogliomas, 15 mixed oligoastrocytomas, 20 anaplastic mixed oligoastrocytomas, and 7 gliosarcomas. The microarray
included normal brain tissue, and AP-2α expression was determined by immunohistochemistry.
Results: AP-2α expression was lost on 99% ( P < 0.001) and 98% ( P < 0.001) of glioblastomas and anaplastic astrocytomas, respectively, compared with grade 2 astrocytomas and normal brain,
all of which (100%) maintained expression of AP-2α. The loss of AP-2α was a negative prognostic indicator within the overall
category of gliomas by univariate analysis (rate ratio, 4.30; 95% confidence interval, 2.60-7.10; P < 0.001). However, there was no significant effect of loss of AP-2α expression on survival observed after adjustment for
patient age, Karnofsky Performance Scale score, tumor grade, and extent of resection (rate ratio, 1.2; 95% confidence interval,
0.6-2.2; P = 0.6).
Conclusions: AP-2α expression correlates inversely with glioma grade, suggesting a direct role in glioma tumorigenicity, possibly through
subsequent deregulation of target genes. Of all the previously characterized markers of progression, the loss of AP-2α would
be the most common (96.2%) molecular marker as an astrocytic tumor evolves from grade 2 to 3.
The incidence of cutaneous malignant melanoma in the United States has increased more than any other cancer in recent years. Chemotherapy for metastatic melanoma is disappointing, there being ...anecdotal cases of complete remission. Dacarbazine (DTIC) is considered the gold standard for treatment, having a response rate of 15-20%, but most responses are not sustained. The mechanisms for the increased chemotherapeutic resistance of melanoma are unclear. The objective of this study was to determine the mechanisms by which melanoma cells escape the cytotoxic effect of DTIC. Here, we show that DTIC induced interleukin (IL)-8 and vascular endothelial growth factor (VEGF) protein overexpression and secretion via transcriptional up-regulation in the two melanoma cell lines SB-2 and MeWo. Luciferase activity driven by the IL-8 and VEGF promoters was up-regulated by 1.5-2- and 1.6-3.5-fold, respectively, in the SB2 and MeWo melanoma cell lines. The mitogen-activated protein kinase signal transduction pathway seemed to regulate at least partially the activation of IL-8, whereas it was not involved in VEGF promoter regulation. Electrophoretic mobility shift analysis analyses have revealed an increase in binding activity of activator protein 1 (c-Jun) and nuclear factor-kappaB after DTIC treatment for both melanoma cell lines. Metastatic melanoma cell lines secreting high levels of IL-8 and VEGF were more resistant to DTIC than early primary melanomas secreting low levels of the cytokines. In addition, transfection of the primary cutaneous melanoma SB-2 cells with the IL-8 gene rendered them resistant to the cytotoxic effect of the drug, whereas the addition of IL-8-neutralizing antibody to metastatic melanoma cells lowered their sensitivity to DTIC. Taken together, our data demonstrate that DTIC can cause melanoma cells to secrete IL-8 and VEGF, which might render them resistant to the cytotoxic effects of the drug. We propose that combination treatment with anti-VEGF/IL-8 agents may potentiate the therapeutic effects of DTIC.
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