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Biomedical subjects

Allan Lipton

Publications and source records attributed to Allan Lipton.

At least 19 recordsLinked to original sources
PubMed2007

Synergistic inhibition of breast cancer cell lines with a dual inhibitor of EGFR-HER-2/neu and a Bcl-2 inhibitor.

The epidermal growth factor receptor (EGFR) (ErbB1) and HER-2/neu (ErbB2) are members of the ErbB family of receptor tyrosine kinases. These receptors are overexpressed in a variety of human tumors and overexpression generally correlates with poor prognosis and decreased survival. Lapatinib, a reversible inhibitor of both EGFR and HER-2/neu, has shown some success in achieving clinical responses in heavily pretreated advanced cancer patients. GW2974 is a reversible dual inhibitor similar to lapatinib, but GW2974 was not progressed to clinical trials due to pharmacokinetic issues. Bcl-2, an anti-apoptotic protein, is also overexpressed in a number of human tumors. Bcl-2 inhibitors induce apoptosis and sensitize cancer cells to other therapies. The purpose of this study was to assess the effects of combining ErbB and Bcl-2 inhibitors on the growth of human breast cancer cell lines. EGFR/HER-2/neu tyrosine kinase inhibitors (lapatinib and GW2974) were combined with Bcl-2 inhibitors (HA14-1 or GX15-070) and the anti-proliferative effects were determined by the MTT tetrazolium dye assay. Combinations were tested in MCF-7 human breast cancer cells, a HER-2/neu transfected MCF-7 cell line (MCF/18), and a tamoxifen-resistant MCF-7 cell line (MTR-3). A synergistic inhibitory effect was observed with the combination of inhibitors of EGFR-HER-2/neu (lapatinib or GW2974) and Bcl-2 (GX15-070 or HA14-1) on the growth of the MCF-7, MCF/18, and MTR-3 human breast cancer cell lines. This study suggests that simultaneously blocking the ErbB family of receptor tyrosine kinases and Bcl-2 family of proteins may be a benefit to breast cancer patients.

Antineoplastic Agents↗
PubMed2006

Serum epidermal growth factor receptor/HER-2 predicts poor survival in patients with metastatic breast cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR, HER-1, and erbB1) is overexpressed in primary breast cancer and had been identified as a poor prognostic factor. METHODS: Pretreatment serum EGFR levels were quantified by using an enzyme-linked immunoadsorbent assay in a Phase III first-line trial of letrozole and tamoxifen and were correlated with patient outcomes. RESULTS: Serum EGFR levels in a control group of 117 healthy, postmenopausal women measured 64.1 +/- 13.3 ng/mL (mean +/- standard deviation). Using a cutoff EGFR level of 44.1 ng/mL from the control group (5% nonparametric method), 53 of 535 patients (10%) had decreased serum levels of EGFR. Patients with decreased serum EGFR had no significant difference in objective response rate (ORR), clinical benefit rate (CBR), time to progression (TTP), or time to treatment failure (TTF); however, they did have significantly reduced survival compared with patients who had normal serum EGFR levels (median survival, 23.3 months vs. 30.9 months; P = .007). A combined analysis of pretreatment serum EGFR and HER-2 yielded no additional predictive information for ORR, CBR, TTP, or TTF compared to serum HER-2 alone. However, in the current analysis, a subgroup of patients who had decreased serum EGFR and normal serum HER-2 was identified (n = 39 of 535 patients; 7.3%) that had significantly reduced survival compared with patients who had normal serum levels of both EGFR and HER-2 (median survival, 23.5 months vs. 37.1 months; P = .005). In multivariate analysis, a decreased serum EGFR level remained a significant independent prognostic factor for decreased survival (hazards ratio, 1.58; P = .007). CONCLUSIONS: In patients who had metastatic breast cancer, decreased serum EGFR/normal serum HER-2 predicted shorter survival compared with patients who had normal levels of serum EGFR/HER-2. This patient subgroup deserves further study to assess their response to and selection for anti-EGFR-directed therapies.

Adult↗
PubMed2006

Future treatment of bone metastases.

All bone surfaces are periodically remodeled by the coupled and balanced action of osteoclasts and osteoblasts, of which the activities are regulated by a variety of cytokines and growth factors. Patients with cancer metastatic to the skeleton often develop osteolytic bone lesions, in which the actions of osteoclasts and osteoblasts remain coupled, but become imbalanced in sites adjacent to the tumor. The result is net bone loss. Many cancers secrete osteoclast-stimulating cytokines, which increase bone resorption by osteoclasts. In turn, factors released from the bone matrix during osteolysis can stimulate tumor growth. In this so-called "vicious cycle," there are multiple sites that are targets for new bone-directed therapies. A variety of new agents for the treatment and prevention of osteolytic bone metastasis are currently being developed. These include new agents that inhibit osteoclast differentiation, bone adhesion, and osteoclast function. These new strategies have evolved from a better understanding of the interaction between tumor cells and cells in the bone marrow microenvironment. There is great promise that these new bone-targeted therapies can decrease the frequent skeletal-related events that greatly diminish quality of life of patients with bone metastases.

Angiogenesis Inhibitors↗
PubMed2006

Advances in treating metastatic bone cancer: summary statement for the First Cambridge Conference.

The First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28 to 29, 2005, was convened to discuss recent advances and research related to the natural history of bone metastases and skeletal complications, bone cancer biology, treatment of myeloma and other solid tumors, and treatment-induced bone loss. The conference format combined brief presentations with extended periods of discussion. The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings.

Bone Neoplasms↗
PubMed2006

Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer.

PURPOSE: To evaluate the relative prognostic value for specific markers of osteoblast and osteoclast activity while controlling for previously reported prognostic variables among men with hormone-refractory metastatic prostate cancer. EXPERIMENTAL DESIGN: The 643 subjects in this report were participants in multicenter randomized controlled trial of zoledronic acid in men with metastatic prostate cancer. All subjects had bone metastases and disease progression despite medical or surgical castration. Relationships between baseline covariates and overall survival were examined by Cox proportional hazard model. Serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide were assessed as representative specific markers of osteoblast and osteoclast activity, respectively. Other covariates in the model were age, log prostate-specific antigen, hemoglobin, lactate dehydrogenase, albumin, analgesic use, and Eastern Cooperative Oncology Group performance status. RESULTS: Serum BAP was significantly correlated with urinary N-telopeptide (correlation coefficient = 0.674; 95% confidence interval, 0.628-0.715; P < 0.0001). In univariate analyses, higher levels of serum BAP and urinary N-telopeptide levels were significantly associated with shorter overall survival. After controlling for the other variables, including N-telopeptide, in multivariate models, higher serum BAP levels were consistently associated with shorter survival. In contrast, urinary N-telopeptide levels were not significantly associated with survival in multivariate analyses. Variables retained in the reduced multivariate model were age, log prostate-specific antigen, hemoglobin, lactate dehydrogenase, analgesic use, and BAP. CONCLUSIONS: Serum BAP significantly correlates with urinary N-telopeptide in men with androgen-independent prostate cancer and bone metastases. In multivariate models, higher levels of serum BAP but not urinary N-telopeptide are associated with shorter overall survival.

Aged↗
PubMed2006

A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.

PURPOSE: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. EXPERIMENTAL DESIGN: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. RESULTS: Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. CONCLUSIONS: A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.

Adult↗
PubMed2006

Biochemical bone markers in breast cancer.

Bone metastases, the most common metastatic manifestation of many cancers, including breast cancer and prostate cancer, contribute significantly to the pain and disability often associated with later stages of malignant disease. Although bisphosphonates have demonstrated efficacy in the treatment of metastatic bone disease (MBD), identifying patients most likely to develop bone metastases (and thus to benefit from treatment) is a challenge. In recent years, advances in understanding the pathophysiologic underpinnings of bone metastases have led to the discovery of several potential markers for dysregulation of bone coupling. Trials have been conducted to validate these biochemical markers and to explore their possible role in measuring efficacy of bisphosphonate treatment and of other metastatic bone therapies. In no area is this research more important than in the management of breast cancer. Although the value of these bone turnover markers is still unclear, and further research is necessary, results from these recent trials indicate some correlation.

Antineoplastic Agents↗
PubMed2005

Serum HER-2/neu conversion to positive at the time of disease progression in patients with breast carcinoma on hormone therapy.

BACKGROUND: Prolonged exposure of breast carcinoma cells in vitro to tamoxifen results in tamoxifen resistance. Tamoxifen-resistant cells express increased HER-2/neu mRNA and protein. The objective of this study was to determine whether patients with metastatic or locally advanced breast carcinoma who have negative serum HER-2/neu status at the initiation of first-line hormone therapy with letrozole or tamoxifen convert to positive serum HER-2/neu status at the time of disease progression and to determine whether serum HER-2/neu conversion to positive status is associated with response to therapy and overall survival. METHODS: Serum samples were obtained at baseline and at the time of disease progression from 240 patients who initially had negative serum HER-2/neu status (< 15 ng/mL). A manual microtiter, enzyme-linked immunosorbent assay that was specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to quantitate serum levels. RESULTS: Among 240 patients, 61 patients (26%) converted from serum HER-2/neu negative to positive (> 15 ng/mL) at the time of disease progression. Thirty-two of 129 patients (25%) who were treated with tamoxifen and 29 of 111 patients (26%) who were treated with letrozole became converted to positive serum HER-2/neu status at the time of disease progression. The response rate and the time to disease progression on first-line hormone therapy were not affected by serum HER-2/neu conversion. The survival of patients who converted to positive serum HER-2/neu status was significantly shorter compared with the survival of patients who remained negative for serum HER-2/neu. A multivariate analysis revealed that conversion to positive serum HER-2/neu status was an independent prognostic variable for survival. CONCLUSIONS: Conversion to positive serum HER-2/neu status occurred in approximately 25% of patients who received first-line hormone therapy. Conversion to serum HER-2/neu-positive status occurred with equal frequency in antiestrogen and aromatase-inhibitor therapy. The current results showed that serum conversion to HER-2/neu-positive status was an independent risk factor for decreased survival in patients with breast carcinoma.

Antineoplastic Agents, Hormonal↗
PubMed2005

Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.

PURPOSE: Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. PATIENTS AND METHODS: Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. RESULTS: Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. CONCLUSION: The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Adult↗
PubMed2005

Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors.

BACKGROUND: Whether bone markers have prognostic value in patients with bone metastases is unknown. We investigated this question in patients with bone metastases secondary to prostate cancer and to non-small-cell lung cancer (NSCLC) and other solid tumors assigned to the placebo arms of two phase III trials of zoledronic acid. METHODS: Levels of the urinary bone resorption marker N-telopeptide and the serum bone formation marker bone-specific alkaline phosphatase were assessed every 3 months for patients with prostate cancer (n = 203) or NSCLC or other solid tumors (n = 238) and were categorized as low or high. Patients were monitored for skeletal-related events, bone disease progression, and death. The relative risks (RRs) and 95% confidence intervals (CIs) for these outcomes were estimated for patients with high versus low levels of each marker using intensity-based multiple event and Cox regression models. All statistical tests were two-sided. RESULTS: In each disease group and overall, high levels of each marker at the beginning of the study were statistically significantly associated with an increased risk of negative outcomes. Use of recent marker assessments as time-dependent covariates gave even greater prognostic significance. High N-telopeptide levels were a stronger prognostic indicator of negative outcomes than bone-specific alkaline phosphatase levels. In recent assessments, patients with high N-telopeptide levels had an increased relative risk of skeletal-related events (prostate cancer, RR = 3.25, 95% CI = 2.26 to 4.68, P<.001; NSCLC and other solid tumors, RR = 1.79, 95% CI = 1.15 to 2.79, P = .010), disease progression (prostate cancer, RR = 2.02, 95% CI = 1.48 to 2.74, P<.001; NSCLC and other solid tumors, RR = 1.91, 95% CI = 1.16 to 3.15, P = .011), and death (prostate cancer, RR = 4.59, 95% CI = 2.82 to 7.46, P<.001; NSCLC and other solid tumors, RR = 2.67, 95% CI = 1.85 to 3.85, P<.001) compared with patients with low N-telopeptide levels. CONCLUSIONS: Baseline and recent bone marker levels were predictive of negative clinical outcomes in patients with bone metastases secondary to prostate cancer and to NSCLC and other solid tumors. N-telopeptide levels were more consistent prognostic indicators than bone-specific alkaline phosphatase for all tumor types, reflecting the key role of osteolysis in the development of skeletal complications.

Adult↗
PubMed2005

Management of bone metastases in breast cancer.

Patients with advanced breast cancer who develop bone metastases suffer an ongoing risk of skeletal complications that can have a significant impact on their quality of life (QoL). These complications include bone pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy (HCM), a potentially life-threatening condition. Treatment options include radiotherapy to palliate bone pain and/or prevent impending fracture, orthopedic surgery to prevent or repair fractures, analgesics, and bisphosphonates, which can significantly reduce the risk of skeletal complications and delay their onset. Of the known bisphosphonates, zoledronic acid is the most potent. Since its regulatory approval in the United States and Europe in 2001, zoledronic acid (4 mg by 15-minute infusion) has become widely used and has replaced pamidronate (90 mg by 2-hour infusion) as the standard of care for treating bone metastases from breast cancer and bone lesions from multiple myeloma. Zoledronic acid has also demonstrated significant long-term benefits in randomized trials in prostate cancer and other solid tumors, whereas other bisphosphonates have failed. In long-term, phase III clinical testing, zoledronic acid provided significant treatment benefits beyond those of pamidronate in patients with breast cancer and demonstrated a safety profile comparable with pamidronate. Therefore, zoledronic acid is now recommended from the first diagnosis of bone metastasis. Other intravenous bisphosphonates include clodronate and ibandronate. Both are approved in Europe, but their efficacy relative to pamidronate and zoledronic acid is not known.

Adult↗
PubMed2005

Zoledronic acid is effective in preventing and delaying skeletal events in patients with bone metastases secondary to genitourinary cancers.

Patients with metastatic bone disease often have severe bone pain and debilitating skeletal complications. Zoledronic acid is the only bisphosphonate shown to be safe and effective in reducing skeletal-related events (SREs), including pathological fractures, spinal cord compression, and radiation or surgery to bone in patients with bone metastases from advanced prostate cancer or renal cell carcinoma (RCC). In both tumour types, zoledronic acid significantly decreased the overall risk of developing an SRE, delayed their onset and significantly reduced the incidence of SREs compared with placebo. In patients with RCC, zoledronic acid also significantly delayed the time to progression of bone lesions by 5 months compared with placebo. Zoledronic acid is safe and well tolerated with long-term use.

Aged↗
PubMed2005

New therapeutic agents for the treatment of bone diseases.

Bisphosphonates have demonstrated important clinical benefits for patients with malignant bone disease, metabolic bone diseases, such as Paget's disease, and postmenopausal osteoporosis. The introduction of nitrogen-containing bisphosphonates with high affinity for hydroxyapatite in bone represents an important advancement. These agents are now a standard of care for osteoporosis, Paget's disease, osteogenesis imperfecta, primary bone lesions from multiple myeloma and bone metastases from breast cancer. Moreover, the recent clinical development of zoledronic acid (4 mg by 15-minute intravenous infusion) has expanded the benefits of bisphosphonate therapy to patients with bone metastases from any solid tumour. Bisphosphonates are also being investigated at present for the prevention of bone loss resulting from cancer therapy. In addition, a variety of novel biologic agents, receptor activator of nuclear factor-kappaB (RANK) ligand antibodies, osteoprotegerin and cathepsin K inhibitors are being investigated at present for the treatment of malignant bone disease. The management of bone health is an important area of active research, and the armamentarium and role of bone-specific therapies continue to expand.

Antineoplastic Agents↗
PubMed2004

Skeletal complications in patients with bone metastases from renal cell carcinoma and therapeutic benefits of zoledronic acid.

Bone metastases in patients with renal cell carcinoma are associated with a high risk of skeletal complications. Therefore, a subset analysis of a larger clinical trial was performed to determine the efficacy of zoledronic acid in renal cell carcinoma patients. Patients with bone metastases from solid tumors other than breast or prostate cancer (n=773) were randomized to receive zoledronic acid or placebo via 15-minute infusion every 3 weeks for 9 months. Patients were monitored for skeletal-related events, which were defined as pathological fracture, spinal cord compression, radiotherapy, or surgery to bone. Among the subset of 74 patients with renal cell carcinoma, 46 patients were treated with 4 mg of zoledronic acid or placebo. Significantly fewer patients treated with 4 mg zoledronic acid had a skeletal-related event (37% versus 74% for placebo, P=0.015), and zoledronic acid significantly prolonged the time to first skeletal-related event (median not reached at 9 months versus 72 days for placebo; P=0.006). Zoledronic acid significantly reduced the annual incidence of skeletal-related events by approximately 21% (mean 2.68 versus 3.38 events per year for placebo, P=0.014) and significantly reduced the risk of developing a skeletal-related event by 61% compared with placebo (risk ratio=0.394, P=0.008) by multiple event analysis. Median time to progression of bone lesions was also significantly extended with zoledronic acid treatment (P=0.014). Zoledronic acid is the first bisphosphonate to significantly reduce skeletal morbidity and significantly prolong time to bone lesion progression in patients with bone metastases from renal cell carcinoma.

Bone Diseases↗
PubMed2004

Toward new horizons: the future of bisphosphonate therapy.

Bisphosphonate therapy has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that bisphosphonates may prevent cancer-treatment-induced bone loss (CTIBL) and the development of malignant bone disease in patients with early-stage cancer. Patients who receive adjuvant hormonal therapy for breast cancer or androgen-deprivation therapy for prostate cancer are at an especially high risk for CTIBL because of reduced estrogenic signaling. Oral clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), oral risedronate (Actonel; Proctor and Gamble Pharmaceuticals, Inc.; Cincinnati, OH), and i.v. zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ) have all demonstrated promise in preventing CTIBL in patients receiving hormonal therapy for breast cancer. Zoledronic acid has demonstrated efficacy with the longest between-treatment interval (3-6 months) and is currently being investigated in the Zometa/Femara Adjuvant Synergy Trials (Z-FAST and ZO-FAST in the United States and Europe, respectively). In patients receiving androgen-deprivation therapy for prostate cancer, i.v. pamidronate (Aredia; Novartis Pharmaceuticals Corp.) and i.v. zoledronic acid both have demonstrated significant benefits over placebo, but only zoledronic acid produced significant increases in bone mineral density compared with baseline values. Additionally, bisphosphonates have demonstrated antitumor activities in preclinical models, and clinical trials with oral clodronate suggest that bisphosphonates might prevent or delay bone metastasis in patients with early-stage breast cancer. Clinical trials are investigating the effect of zoledronic acid on disease progression in patients with breast cancer, prostate cancer, and non-small cell lung cancer. The results of these clinical trials should further define the clinical benefit of bisphosphonates in the oncology setting.

Bone Neoplasms↗