scholarly journals The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Abena B. Redwood ◽  
Xiaomei Zhang ◽  
Sahil B. Seth ◽  
Zhongqi Ge ◽  
Wendy E. Bindeman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stress Tolerance ◽  
Single Agent ◽  
Predictive Biomarkers ◽  
Replication Stress ◽  
Drop Out ◽  
Cluster Assembly ◽  
Breast Cancer Patients ◽  
Global Comparison ◽  
Iron Sulfur

AbstractThe relationship between ATR/Chk1 activity and replication stress, coupled with the development of potent and tolerable inhibitors of this pathway, has led to the clinical exploration of ATR and Chk1 inhibitors (ATRi/Chk1i) as anticancer therapies for single-agent or combinatorial application. The clinical efficacy of these therapies relies on the ability to ascertain which patient populations are most likely to benefit, so there is intense interest in identifying predictive biomarkers of response. To comprehensively evaluate the components that modulate cancer cell sensitivity to replication stress induced by Chk1i, we performed a synthetic-lethal drop-out screen in a cell line derived from a patient with triple-negative breast cancer (TNBC), using a pooled barcoded shRNA library targeting ~350 genes involved in DNA replication, DNA damage repair, and cycle progression. In addition, we sought to compare the relative requirement of these genes when DNA fidelity is challenged by clinically relevant anticancer breast cancer drugs, including cisplatin and PARP1/2 inhibitors, that have different mechanisms of action. This global comparison is critical for understanding not only which agents should be used together for combinatorial therapies in breast cancer patients, but also the genetic context in which these therapies will be most effective, and when a single-agent therapy will be sufficient to provide maximum therapeutic benefit to the patient. We identified unique potentiators of response to ATRi/Chk1i and describe a new role for components of the cytosolic iron–sulfur assembly (CIA) pathway, MMS19 and CIA2B-FAM96B, in replication stress tolerance of TNBC.

scholarly journals The role of abemaciclib in treatment of advanced breast cancer

2018 ◽  
Vol 10 ◽  
pp. 175883591877692 ◽  
Author(s):  
Amelia McCartney ◽  
Erica Moretti ◽  
Giuseppina Sanna ◽  
Marta Pestrin ◽  
Emanuela Risi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Single Agent ◽  
Endocrine Resistance ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Significant Activity ◽  
Epidermal Growth

Until recently, the mainstay of treatment in the majority of hormone receptor (HR)-positive, human epidermal growth factor 2 receptor (HER2)-negative advanced breast cancer (ABC) has consisted of single-agent endocrine therapy (ET). However, as understanding of endocrine resistance has grown, newer targeted agents have come to the fore. Inhibition of cyclin-dependent kinase complexes 4 and 6 (CDK4/6) combined with ET has shown significant activity in HR+ HER2− ABC, with impressive results in terms of progression-free survival (PFS) when compared with ET alone. This review summarizes the seminal findings pertaining to CDK4/6 inhibition in this population, specifically focusing on abemaciclib, contrasted with palbociclib and ribociclib. Potential directions for future studies are discussed, as a way of addressing outstanding issues such as establishing optimal treatment sequencing and agent combinations, appropriate patient selection to derive maximal benefits, predictive biomarkers and the employment of CDK4/6 inhibition beyond the ABC setting.

Vinorelbine as Single Agent in Pretreated Patients with Advanced Breast Cancer

1994 ◽  
Vol 80 (4) ◽  
pp. 280-282 ◽  
Author(s):  
Sandro Barni ◽  
Antonio Ardizzoia ◽  
Gianni Bernardo ◽  
Silvia Villa ◽  
Maria Rosa Strada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Cancer Patients ◽  
Performance Status ◽  
Single Agent ◽  
Vinca Alkaloid ◽  
Advanced Breast ◽  
Weekly Dose ◽  
Weekly Schedule ◽  
Breast Cancer Patients

Vinorelbine is a new semisynthetic vinca alkaloid with high activity against breast cancer. In this multicenter clinical study we evaluated the activity and toxicity of vinorelbine as a single agent in 30 advanced breast cancer patients pretreated with anthracycline and/or mitoxantrone (24 with recurrent tumor, 6 with non operable cancers). Vinorelbine was given at a weekly dose of 20 mg/m2 for a minimum of 3 weeks. Treatment was continued until there was disease progression or evidence of serious toxicity. Predominant sites of metastasis were viscera (14 cases), soft tissue (11 cases) and bone (5 cases). A median number of 12 doses of vinorelbine (range 3-34) were administered to each patient. Objective responses were recorded in 11 of them and 15 had minimal responses or stable disease. Four patients showed progression of disease during vinorelbine chemotherapy. The median duration of response was 5 months (2-14). The median survival time was 7 months (2-20+): 9 months for responders and 5 months for those with stable or progressive disease. The most important and dose-limiting toxicity was represented by leukopenia. The compliance of patients was very good and the treatment was well accepted by them all including those with low performance status. In conclusion, this study provides further evidence that a weekly schedule with vinorelbine as a single agent is effective and well-tolerated also in pretreated advanced breast cancer patients.

Safety and Efficacy of Using a Single Agent or a Phase II Agent Before Instituting Standard Combination Chemotherapy in Previously Untreated Metastatic Breast Cancer Patients: Report of a Randomized Study—Cancer and Leukemia Group B 8642

1999 ◽  
Vol 17 (5) ◽  
pp. 1397-1397 ◽  
Author(s):  
Mary E. Costanza ◽  
Raymond B. Weiss ◽  
I. Craig Henderson ◽  
Larry Norton ◽  
Donald A. Berry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Single Agent ◽  
Metastatic Breast ◽  
Response Rates ◽  
Breast Cancer Patients ◽  
Safety And Efficacy

PURPOSE: We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF. RESULTS: The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm. CONCLUSION: The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.

Phase II study of goserelin for patients with postmenopausal metastatic breast cancer.

1993 ◽  
Vol 11 (8) ◽  
pp. 1529-1535 ◽  
Author(s):  
T Saphner ◽  
A B Troxel ◽  
D C Tormey ◽  
D Neuberg ◽  
N J Robert ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Response Rate ◽  
Single Agent ◽  
Metastatic Breast ◽  
Postmenopausal Breast Cancer ◽  
Complete Response ◽  
Serum Levels ◽  
Breast Cancer Patients ◽  
Before And After

PURPOSE To determine the response rate of postmenopausal breast cancer patients to the gonadotropin-releasing hormone (GN-RH) agonist, Zoladex (goserelin; ICI Pharma, Wilmington, DE). PATIENTS AND METHODS A multi-institutional single-agent trial in postmenopausal patients was conducted. Serum levels of follicle-stimulating hormone (FSH), testosterone, and estradiol were requested before and after Zoladex treatment. RESULTS For estrogen receptor-positive (ER+) patients, the response rate was 11%, with one complete response (CR) and three partial responses (PRs) among 36 eligible patients. Responses were of short duration. There were no responses among 16 estrogen receptor-negative (ER-) patients. CONCLUSION GN-RH agonists have activity in ER+ postmenopausal patients, but response rates are not as high as with other available endocrine therapies and the duration of response is short.

Oral vinorelbine plus capecitabine (oral vincap) combination in patients with advanced breast cancer (ABC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10673-10673
Author(s):  
V. Lorusso ◽  
M. Spada ◽  
M. Giampaglia ◽  
A. Misino ◽  
R. Calabrese ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Advanced Breast Cancer ◽  
Single Agent ◽  
Advanced Breast ◽  
Survival Duration ◽  
Breast Cancer Patients ◽  
Peripheral Neurotoxicity ◽  
Oral Vinorelbine ◽  
Median Response

10673 Background: Vinorelbine i.v. and capecitabine are two of the most effective single agents in previously treated advanced breast cancer (ABC). A number of studies have been reported with the combination of these agents. Actually, the availability of oral formulation for vinorelbine allows a full oral combination of the two agents. The aim of this study was to evaluate the activity and toxicity of this novel combination. Patients and Methods: Thirty-eight advanced breast cancer patients (pts) refractory to anthracyclines and taxanes were included in this study. Treatment consisted of vinorelbine 60 mg/m2 (days 1 + 8), and capecitabine 2000 mg/m2 (days 2–7 and 9–16) every 3 weeks. The pt characteristics were: median age 53 years (range 37–77 years); ECOG PS 0–1 in 35 pts (92.1%), and PS 2 in 3 pts (7.8%); ER+/PgR+ 20 pts (52.6%) and ER−/PgR− 11 pts (28.9%). Dominant sites of disease were visceral in 19 pts (50.0%), bone in 10 pts (26.3%), soft tissue in 9 pts (23.6%). Results: A total of 228 courses were given with a mean of three cycles/pt (range 1–12). Five pts (13.1%) had no toxicity at all. Hematologic side-effects were: neutropenia G2-G3 in 7 pts (18.9%), and G4 in 1 pt (2.7%), anemia G1 in 11 pts (29.7%), G2-G3 in 5 pts (13.5%), thrombocytopenia G1 in 6 pts (16.2%) and G3 in 1 pt (2.7%). Non-hematologic side-effects were: fatigue G1 in 5 pts (13.5%), hand-foot syndrome G1 in 2 pt (5.4%) and G2 in 2 pts (5.4%), nausea/vomiting G1 in 2 pts (5.4%), G2 in 3 pts (8.1%) and G3 in 1 pt (2.7%), constipation G1 in 2 pts (5.4%), peripheral neurotoxicity G1 in 3 pts (8.1%) and G2 in 1 pt (2.7%), gastric pain G1 in 2 pts (5.4%), stomatitis G1 in 3 pts (8.1%) and G2 in 1 pt (2.7%). Out of 38 pts assessable, we observed 2 (5.4%) CR, 13 (34 %) PR, 14 (37.8%) SD, and 9 (26.3%) PD. The median time to progression was 4.5 months (range 1–18 months), the median response duration was 7 months (range 2–18 months), and the median survival duration was 10 months (range 2–26+). Conclusions: The oral vincap combination was well tolerated and effective in ABC. In fact, this regimen achieved results comparable to the previously reported combinations of capecitabine and i.v. vinorelbine. The oral vincap should be considered as an alternative to single agent capecitabine or vinorelbine in ABC refractory to antra-taxane combination. No significant financial relationships to disclose.

Nanoparticle albumin-bound (Nab) paclitaxel (P) in combination with bevacizumab (B) with and without gemcitabine (G): Early experience at the Braman Family Breast Cancer Institute

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10748-10748
Author(s):  
C. F. Lobo ◽  
G. Lopes ◽  
O. Silva ◽  
S. Gluck
Keyword(s):  
Breast Cancer ◽  
Single Agent ◽  
Metastatic Breast ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Hemorrhagic Complication ◽  
Breast Cancer Patients ◽  
Hormone Receptor Positive ◽  
Heavily Pretreated ◽  
Grade 3

10748 Background: Nab-P improves outcomes when compared against single agent cremophor-based P, as does the addition of bevacizumab or gemcitabine to the same agent. There are no available data regarding combinations of Nab-P with B and/or G. Ongoing investigational efforts are evaluating various doublets with these agents, but, to the best of our knowledge, not all 3 of them in the same regimen. All drugs are currently FDA-approved in the treatment of breast cancer. Methods: Review of single-institution experience, evaluating safety and preliminary evidence of activity with the use of Nab-P and B with and without G in heavily pretreated her2neu negative metastatic breast cancer patients. Assessment of response was undertaken by the investigators independently of treating physician. RECIST criteria were used. Three patients received Nab-P and B at the following doses: Nab-P 100 mg/m2, B 10 mg/kg every 2 weeks, and 2 patients received all 3 drugs as follows: Nab-P 100 mg/m2, G 1,000 mg/m2, B 10 mg/kg every 2 weeks. Results: Five women have been evaluated. Median age was 51 (range 34–69). Two patients had hormone-receptor positive disease and 3 had ER/PR/Her2neu-negative cancer. Prior number of regimens was 3 (range 2–7). Four patients had been treated with a taxane. One received both paclitaxel and docetaxel, and 3 docetaxel only. A median of 5 cycles have been administered (range 3–9). First-cycle grade 3/4 toxicity was seen in only one patient who had a baseline grade 2 thrombocytopenia that progressed to grade 3. The thrombocytopenia resolved without requiring transfusion and without any hemorrhagic complication. Another patient developed grade 2 peripheral neuropathy. Two patients are not yet assessable for response. At time of first evaluation 1 patient had progressive disease (Nab-P, B; 7 prior lines of treatment), one had stable disease (Nab-P, B, G; 3 prior lines of therapy, including docetaxel), and 1 had a partial response (Nab-P, B, G; 2 prior therapies, including docetaxel). Conclusions: These very preliminary data suggest that Nab-P in combination with B with and without G is a safe regimen and formal Phase I/II trials are being developed to confirm its clinical activity. [Table: see text]

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