Philippe R. Montgrain

Prognostic Implications of Parathyroid Hormone-Related Protein in Males and Females With Non–Small-Cell Lung Cancer

BACKGROUND Non-small-cell lung carcinoma immunoreactivity for parathyroid hormone-related protein has been associated with increased survival in female patients but not in male patients. The current investigation attempted to substantiate this finding in 2 new patient groups. METHODS Patients were divided into groups with and without immunoreactivity for a carboxyl-terminal parathyroid hormone-related protein epitope assessed in deparaffinized sections by a blinded observer. One group included 85 female patients with stage I lung cancer, and the second group had 48 female and 66 male patients with stage I-IV lung cancer. Survival times were compared by the log-rank test between groups separated by tumor parathyroid hormone-related protein status. RESULTS Parathyroid hormone-related protein was present in 70%-80% of the patients, independent of sex, stage, and smoking history. In the females with stage I lung cancer, parathyroid hormone-related protein increased median survival from 25 to 60 months (P < .05). In the second group, parathyroid hormone-related protein expression increased 48-month disease-free survival of female lung cancer patients from 44% to 63% (P < .05), but had no effect in male patients. Parathyroid hormone-related protein remained a significant, independent predictor when evaluated together with other covariates by Cox multivariate regression. CONCLUSION This study verifies that parathyroid hormone-related protein is a sex-dependent survival factor for non-small-cell lung carcinoma, that it correlates with disease-free survival, and that the association with survival holds for women with early-stage disease as well as more advanced cancer. Thus, the protein could find use as a prognostic indicator and could be a target for therapy.

Parathyroid Hormone-Related Protein Varies With Sex and Androgen Status in Nonsmall Cell Lung Cancer

In nonsmall cell lung cancer, tumor parathyroid hormone‐related protein (PTHrP) expression predicts longer survival in women but not in men. To explain the sex‐dependent survival effect, the authors proposed that hormonal influences decrease PTHrP in men versus women, that PTHrP inhibits tumor growth, and that the effect is greater in women than in men. The objectives of this study were to compare lung carcinoma PTHrP expression and carcinoma growth in male and female mice and to determine whether gonadal steroids regulate PTHrP in lung cancer cells.

Combinatorial library discovery of small molecule inhibitors of lung cancer proliferation and parathyroid hormone-related protein expression

PTHrP (parathyroid hormone-related protein) is abnormally expressed in a substantial majority of lung cancers, especially non-small cell lung cancers, and plays a key role in tumor progression. Thus, this oncoprotein could be a target for treating patients with lung cancer. This study screened combinatorial libraries of heterocyclic amines for inhibitory effects on PTHrP expression and cell proliferation. Two libraries of over 780,000 bis-cyclic thiourea and guanidine compounds each were tested in BEN lung carcinoma cells. The number of PTHrP inhibitors and the magnitude of the reduction in PTHrP were greater for thioureas. Selected lead thiourea compounds decreased cell PTHrP protein content in dose-dependent fashion, reduced relative abundance of PTHrP mRNA, decreased transcripts derived from the PTHrP P3 promoter and reduced activity of a full length PTHrP promoter luciferase construct. Similar effects on PTHrP mRNA were observed in A549 and H441 lung adenocarcinoma cells and in H727 lung carcinoid cells. However, the compounds only inhibited PTHrP protein levels in BEN cells and H727 cells. The compounds reduced the rate of cell proliferation in BEN cells and H727 cells, but not in lines that showed no inhibition of PTHrP protein. These results suggest that cyclic thiourea compounds inhibit PTHrP expression mediated by the P3 promoter, which is widely used in the majority of PTHrP-expressing cells, and that they may inhibit growth of lung cancer cells through the same mechanism. Further work will be necessary to investigate their mechanism for effects on growth of PTHrP-positive tumors in vivo.

Cell cycle actions of parathyroid hormone-related protein in non-small cell lung carcinoma.

Parathyroid hormone-related protein (PTHrP), a paraneoplastic protein expressed by two-thirds of human non-small cell lung cancers, has been reported to slow progression of lung carcinomas in mouse models and to lengthen survival of patients with lung cancer. This study investigated the effects of ectopic expression of PTHrP on proliferation and cell cycle progression of two human lung adenocarcinoma cell lines that are normally PTHrP negative. Stable transfection with PTHrP decreased H1944 cell DNA synthesis, measured by thymidine incorporation, bromodeoxyuridine uptake, and MTT proliferation assay. A substantial fraction of PTHrP-positive cells was arrested in or slowly progressing through G1. Cyclin D2 and cyclin A2 protein levels were 60-70% lower in PTHrP-expressing cells compared with control cells (P < 0.05, N = 3 independent clones per group), while expression of p27(Kip1), a cyclin-dependent kinase inhibitor, was increased by 35 +/- 9% (mean +/- SE, P < 0.05) in the presence of PTHrP. Expression of other cyclins, including cyclins D1 and D3, and cyclin-dependent kinases was unaffected by PTHrP. PTHrP did not alter the phosphorylation state of Rb, but decreased cyclin-dependent kinase (CDK) 2-cyclin A2 complex formation. Ectopic expression of PTHrP stimulated ERK phosphorylation. In MV522 cells, PTHrP had similar effects on DNA synthesis, cyclin A2 expression, pRb levels, CDK2-cyclin A2 association, and ERK activation. In summary, PTHrP appears to slow progression of lung cancer cells into S phase, possibly by decreasing activation of CDK2. Slower cancer cell proliferation could contribute to slower tumor progression and increased survival of patients with PTHrP-positive lung cancer.

Time to treatment and survival in veterans with lung cancer eligible for curative intent therapy

BACKGROUND The Institute of Medicine emphasizes care timeliness as an important quality metric. We assessed treatment timeliness in stage I-IIIA lung cancer patients deemed eligible for curative intent therapy and analyzed the relationship between time to treatment (TTT) and timely treatment (TT) with survival. METHODS We retrospectively reviewed consecutive cases of stage I-IIIA lung cancer deemed eligible for curative intent therapy at the VA San Diego Healthcare System between 10/2010-4/2017. We defined TTT as days from chest tumor board to treatment initiation and TT using guideline recommendations. We used multivariable (MVA) Cox proportional hazards regressions for survival analyses. RESULTS In 177 veterans, the median TTT was 35 days (29 days for chemoradiation, 36 for surgical resection, 42 for definitive radiation). TT occurred in 33% or 77% of patients when the most or least timely guideline recommendation was used, respectively. Patient characteristics associated with longer TTT included other cancer history, high simplified comorbidity score, stage I disease, and definitive radiation treatment. In MVA, TTT and TT [HR 0.53 (95% CI 0.27, 1.01) for least timely definition] were not associated with OS in stage I-IIIA patients, or disease-free survival in subgroup analyses of 122 stage I patients [HR 1.49 (0.62, 3.59) for least timely definition]. CONCLUSION Treatment was timely in 33-77% of veterans with lung cancer deemed eligible for curative intent therapy. TTT and TT were not associated with survival. The time interval between diagnosis and treatment may offer an opportunity to deliver or improve other cancer care.

Lung carcinoma progression and survival versus amino- and carboxyl-parathyroid hormone-related protein expression

PurposeExpression of the carboxyl PTHrP region of parathyroid hormone-related protein (PTHrP) is a positive prognostic indicator in women with lung cancer, but amino PTHrP is a negative indicator in other lung cancer patients. This project investigated whether PTHrP could be expressed as predominantly amino PTHrP or carboxyl PTHrP in individual lung carcinomas. It also assessed domain-specific effects on cancer progression and patient survival.MethodsPTHrP immunoreactivities were analyzed versus survival in a human lung cancer tissue microarray (TMA). Growth was compared in athymic mice for isogenic lung carcinoma xenografts differing in expression of amino and carboxyl PTHrP domains.ResultsIn the TMA, 33 of 99 patient tumors expressed only one PTHrP domain, while 54 expressed both. By Cox regression, the hazard ratio for cancer-specific mortality (95% confidence interval) was 2.6 (1.28–5.44) for amino PTHrP (P = 0.008) and 0.6 (0–2.58) for carboxyl PTHrP (P = 0.092). Xenografts of H358 lung adenocarcinoma cells that overexpressed amino PTHrP grew twice as fast as isogenic low PTHrP tumors in athymic mice, but growth of tumors expressing amino plus carboxyl PTHrP was not significantly different than growth of the control tumors. In summary, the presence of amino PTHrP signifies worse prognosis in lung cancer patients. In mouse xenografts, this effect was abrogated if carboxyl PTHrP was also present.ConclusionAmino PTHrP and carboxyl PTHrP can vary independently in different lung carcinomas. Carboxyl PTHrP may temper the stimulatory effect of amino PTHrP on cancer progression.

Parathyroid Hormone–Related Protein in the Healthy and Injured Lung

Parathyroid hormone–related protein (PTHrP) is an oncofetal protein with functional effects in normal and diseased lung. In the respiratory system, the hormone has implications for a variety of processes, including lung development, alveolar type II cell function and differentiation, cell proliferation, apoptosis, motility, and matrix interactions. PTHrP regulates branching morphogenesis and type II cell maturation in fetal lung through bidirectional interactions with lung fibroblasts. Consequently, it appears to have a role in the pathophysiology of respiratory distress syndrome and bronchopulmonary dysplasia. In adult lung, the molecule has autocrine actions on type II pneumocytes that stimulate phosphatidylcholine production, inhibit cell proliferation, and sensitize to apoptotic stimuli. Type II cell PTHrP levels fall after lung injury, inversely coordinated in time with their proliferation, suggesting that reduction in its growth inhibitory effect may contribute to the increase in type II cell number...