Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines

Introduction: Overexpression of the receptor tyrosine kinase HER2 has been reported in around 25% of human breast cancers, usually indicating a poor prognosis. As a result, HER2 has become a popular target for therapy. However, despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments. It is therefore important to understand the underlying mechanism of resistance and to develop more effective therapeutic interventions for breast cancer. Methods: The sensitivity of a panel of seven breast cancer cell lines to treatment with various types HER-family inhibitors alone, or in combination with a selection of other tyrosine kinase inhibitors (TKIs) or chemotherapeutic agents was determined using the Sulforhodamine B colorimetric assay. Receptor expression, cell-cycle distribution, cell signalling and cell migration were determined using flow cytometry, Western blot and Incucyte Zoom Live-Cell Analysis System respectively. Results: Overall, breast cancer cells were more sensitive to treatment with the irreversible pan-HER family inhibitors, particularly afatinib and neratinib, than treatment with the first-generation reversible inhibitors. Of three HER-2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors (IC50s as low as 3 nM), while MDA-MB-453 was relatively resistant (lowest IC50 = 0.11 μM). When the HER-family inhibitors were combined with other agents such as NVP-AEW541 (an IGF-1R inhibitor), dasatinib (a Src inhibitor) or crizotinib (a c-Met/ALK inhibitor), such combination produced synergistic effects in some of the cell lines examined. Interestingly, co-targeting of Src and HER-family members in MDA-MB-453 cells led to synergistic growth inhibition, suggesting the importance of Src in mediating resistance to HER2-targeting agents. Finally, treatment with the irreversible HER family blockers and dasatinib were also most effective at inhibiting the migration of breast cancer cells. Conclusion: We concluded that the irreversible inhibitors of HER-family members are generally more effective at inhibiting growth, downstream signalling and migration compared with reversible inhibitors, and that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation

ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-Induced Peripheral Neuropathy in Black Women With Early-Stage Breast Cancer

PURPOSE: Black women experience higher rates of taxane-induced peripheral neuropathy (TIPN) compared with White women when receiving adjuvant once weekly paclitaxel for early-stage breast cancer, leading to more dose reductions and higher recurrence rates. EAZ171 aimed to prospectively validate germline predictors of TIPN and compare rates of TIPN and dose reductions in Black women receiving (neo)adjuvant once weekly paclitaxel and once every 3 weeks docetaxel for early-stage breast cancer. METHODS: Women with early-stage breast cancer who self-identified as Black and had intended to receive (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel were eligible, with planned accrual to 120 patients in each arm. Genotyping was performed to determine germline neuropathy risk. Grade 2-4 TIPN by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was compared between high- versus low-risk genotypes and between once weekly paclitaxel versus once every 3 weeks docetaxel within 1 year. Patient-rated TIPN and patient-reported outcomes were compared using patient-reported outcome (PRO)-CTCAE and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity. RESULTS: Two hundred and forty of 249 enrolled patients had genotype data, and 91 of 117 (77.8%) receiving once weekly paclitaxel and 87 of 118 (73.7%) receiving once every 3 weeks docetaxel were classified as high-risk. Physician-reported grade 2-4 TIPN was not significantly different in high- versus low-risk genotype groups with once weekly paclitaxel (47% v 35%; P = .27) or with once every 3 weeks docetaxel (28% v 19%; P = .47). Grade 2-4 TIPN was significantly higher in the once weekly paclitaxel versus once every 3 weeks docetaxel arm by both physician-rated CTCAE (45% v 29%; P = .02) and PRO-CTCAE (40% v 24%; P = .03). Patients receiving once weekly paclitaxel required more dose reductions because of TIPN (28% v 9%; P < .001) or any cause (39% v 25%; P = .02). CONCLUSION: Germline variation did not predict risk of TIPN in Black women receiving (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel. Once weekly paclitaxel was associated with significantly more grade 2-4 TIPN and required more dose reductions than once every 3 weeks docetaxel

A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results

Background SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. Patients and methods Women aged ≥18 years with metastatic or recurrent ER+, HER2− breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. Results By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. Conclusions Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298)

Camizestrant in combination with three globally approved CDK4/6 inhibitors in women with ER+, HER2- advanced breast cancer: Results from SERENA-1.

Purpose: This trial investigated the safety and tolerability of camizestrant with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in women with estrogen receptor–positive, HER2− advanced breast cancer. Patients and Methods: SERENA-1 (NCT03616587) is a phase I, multipart, open-label study in women with refractory estrogen receptor–positive, HER2− advanced breast cancer. Patients received oral once-daily camizestrant 75 or 150 mg plus abemaciclib; camizestrant 75, 150, or 300 mg plus palbociclib; or camizestrant 75 mg plus ribociclib 400 or 600 mg. Safety/tolerability, pharmacokinetics, efficacy, and impact on estrogen receptor 1 mutation ctDNA were assessed. Results: By September 16, 2024 (data cutoff), 53 patients had received camizestrant plus abemaciclib, 78 camizestrant plus palbociclib, and 60 camizestrant plus ribociclib. Patients had a median of 2 (range, 0–7) prior regimens for advanced disease; 83% had received a prior CDK4/6i and 59% prior fulvestrant. The most common treatment-emergent adverse events for camizestrant 75 mg (phase III dose) plus each CDK4/6i were diarrhea [with abemaciclib (87.5%)] and neutropenia [with palbociclib (80%) and ribociclib (32.1% for 400 mg and 53.1% for 600 mg)]. The median camizestrant tmax was ∼4 hours postdose across combinations, with an estimated half-life of 9.5 to 17 hours. No clinically meaningful drug–drug interactions were evident. In this heavily pretreated population, CBR24 was 49.5% and the median progression-free survival was 7.4 months (95% confidence interval, 5.3–9.3), with antitumor activity across all combinations, including patients previously treated with CDK4/6i and/or fulvestrant, with or without estrogen receptor 1 mutation. Conclusions: Camizestrant is well tolerated, with antitumor activity in combination with CDK4/6i. These results support the evaluation of camizestrant 75 mg plus standard CDK4/6i doses in phase III trials

Expanding frontiers in materials chemistry and physics with multiple anions

During the last century, inorganic oxide compounds laid foundations for materials synthesis, characterization, and technology translation by adding new functions into devices previously dominated by main-group element semiconductor compounds. Today, compounds with multiple anions beyond the single-oxide ion, such as oxyhalides and oxyhydrides, offer a new materials platform from which superior functionality may arise. Here we review the recent progress, status, and future prospects and challenges facing the development and deployment of mixed-anion compounds, focusing mainly on oxide-derived materials. We devote attention to the crucial roles that multiple anions play during synthesis, characterization, and in the physical properties of these materials. We discuss the opportunities enabled by recent advances in synthetic approaches for design of both local and overall structure, state-of-the-art characterization techniques to distinguish unique structural and chemical states, and chemical/physical properties emerging from the synergy of multiple anions for catalysis, energy conversion, and electronic materials

Designing New Magnesium-Based Cathode Materials

Lithium-ion batteries have been a mainstay of the consumer electronics industries for nearly 25 years. Unlike many older energy storage systems, lithium-ion does not describe a specific chemistry but a family of chemistries and a mechanism of operation. As a result numerous types of materials are under the umbrella of lithium-ion batteries that can be modified and developed to meet a variety of end-user goals. Looking beyond-lithium ion, the landscape is less understood and explored. One of our research efforts is to look at non-lithium cation based energy storage chemistries, including the MgxV2O5 and MgxV2O5*H2O systems. This talk will focus on recent developments from our lab in Mg-ion and Ca-ion chemistries with highlighting new types of cathodes, electrolytes, and anode materials1-5 References (1) Lipson, A.L; Han, S.-D; Kim, S. Pan, BF; Sa, N.; Liao; C, Fister, TT; Burrell, AK; Vaughey, JT; Ingram, BJ J. Power Sources 325 646-652 (2016). (2) Sa, N; Wang, H; Proffit, DL; Lipson, AL; Key, B; Liu, M; Feng, ZX; Fister, TT; Ren, Y; Sun, CJ; Vaughey, JT; Fenter, PA; Persson, KA; Burrell, AK J. Power Sources 323 44-50 (2016). (3) Sa, N; Kinnibrugh, TL; Wang, H; Gautam, GS; Chapman, KW; Vaughey, JT; Key, B; Fister, TT; Freeland, JW; Proffit, DL; Chupas, PJ; Ceder, G; Bareno, JG; Bloom, ID; Burrell, AK Chemistry of Materials, 28(9) 2962-2969 (2016). (4) Lipson, AL; Han, SD; Pan, B; See, KA; Gewirth, AA; Liao; Vaughey, J; Ingram, BJ J. Electrochem. Soc., 163(10) A2253-A2257 (2016). (5) Mukherjee, A.; Sa, N.; Phillips, P.; Burrell, AK; Vaughey, JT; Klie, R. Chemistry of Materials, 29, 2218−2226 (2017). Figure 1 <jats:p /

Clinical application of coronary sinus retroperfusion during high risk percutaneous transluminal coronary angioplasty

AbstractObjectives. This study was designed to determine the efficacy of synchronized coronary sinus retroperfusion of arterial blood in reducing myocardial ischemia associated with the performance of high risk coronary angioplasty.Background. Previous animal and clinical work has demonstrated the efficacy of this technique in supporting ischemic myocardium.Methods. Twenty-one patients were randomized to alternately receive coronary sinus retroperfusion support during either the second or the third coronary angioplasty balloon inflation, after an initial unsupported brief control inflation. Myocardial ischemia was assessed by the extent of echocardiographic left ventricular wall motion abnormality, quantified ST segment deviation and hemodynamic and anginal variables during balloon inflations performed with and without coronary sinus retroperfusion support. Regional wall motion score was defined as hyperkinesia (−1), normokinesia (0), hypokinesia (+1), akinesia (+2) and dyskinesia (+3).Results. A reduction in the echocardiographic left anterior descending regional wall motion score in retroperfusion-supported (1.7 ± 2.1) versus unsupported (2.7 ± 1.6) inflations (p < 0.05) was noted. Twelve-lead electrocardiographic monitoring revealed no additional ST segment deviation during supported (173 ± 95 s) compared with unsupported (129 ± 87 s) angioplasty inflations despite a significantly longer duration of supported inflations (p < 0.004). Mean and peak systolic coronary sinus pressures differed during supported inflations (21 ± 6 and 44 ± 13 mm Hg) versus unsupported inflations (10 ± 4 and 16 ± 5 mm Hg) (p < 0.001). There was no difference in hemodynamic or anginal variables.Conclusions. A reduction in ischemia as defined by wall motion abnormality during retroperfusion-supported compared with unsupported angioplasty balloon inflations was documented. No additional ST segment deviation occurred during retroperfusion-supported compared with unsupported balloon inflations despite a significantly longer duration of supported inflations. No difference in hemodynamic or anginal variables was noted

A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298)