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Целенаправленная деградация белка разрушает ненаркомные цели, чтобы обратить вспять иммунное уклонение и терапию устойчивости к раку.

Таргетированная деградация белков (ТД) использует эндогенные протеолитические системы — систему убиквина и протеасомы и лизосомальные пути — для селективного удаления белков, вызывающих болезни, которые не реагируют на традиционное ингибирование. В онкологической иммунотерапии ТД разрушает критические иммунодепрессивные узлы в экзоцитоплазматическом, мембранном и цитоплазматическом компартментах, перепрограммируя микросреду опухоли от иммунологически «холодной» к «горячей» состоянию. Эта статья рассматривает молекулярные принципы инженерии бифункциональных деградаторов и обобщает клинические д

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… The standard agent fulvestrant achieves only 50%–60% ER degradation in the clinic, falling short of therapeutic needs. … Another oral SERD, camizestrant, also showed superior PFS over fulvestrant in the phase II SERENA-2 trial ( NCT04214288 ) (7.2–7.7 vs 3.7 months; HR 0.59–0.64) ( 100 ). …

Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience.

Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts' immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The

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… Aurilio et al. used CM with fulvestrant, which resulted with prolonged CB [ 62 ]. The aim of metronomic treatment is not solely palliative treatment; neoadjuvant setting is an active area of investigation. … In hormone receptor positive tumors, conventional scheme of fulvestrant was added to capecitabine in 41 patients; CB of 58.1% was obtained with 14.9 months' median PFS [ 76 ]. …

Bone-Targeted Agents in Breast Cancer: Do We Now Have All the Answers?

The bone-targeted agents (BTAs), bisphosphonates and denosumab, have an established role in the treatment of metastatic breast cancer bone disease and the prevention of cancer-treatment-induced bone loss. Evidence in support of their ability to improve survival in early breast cancer now indicates that the bisphosphonates are effective in postmenopausal women (naturally or chemically induced), but denosumab does not have similar benefits when added to standard adjuvant therapy. In postmenopausal women with early breast cancer, the choice of BTA may differ depending on the indication for treatm

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… directly into mouse tibiae | Ko et al 41 | | Combining zoledronic acid with halofuginone enhances the inhibition of breast cancer bone metastasis and compares with either drug alone | Juarez et al 42 Oestrogen receptor positive MCF7 | Immune compromised | Zoledronic acid increased anti-tumour effects of fulvestrant … Zoledronic acid sensitizes breast cancer cells to fulvestrant via ERK/HIF-1 pathway inhibition in vivo . …

Advances in Diet and Physical Activity in Breast Cancer Prevention and Treatment.

There is currently a growing interest in diets and physical activity patterns that may be beneficial in preventing and treating breast cancer (BC). Mounting evidence indicates that indeed, the so-called Mediterranean diet (MedDiet) and regular physical activity likely both help reduce the risk of developing BC. For those who have already received a BC diagnosis, these interventions may decrease the risk of tumor recurrence after treatment and improve quality of life. Studies also show the potential of other dietary interventions, including fasting or modified fasting, calorie restriction, keto

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… We found MF to markedly delay acquired resistance to tamoxifen and fulvestrant in MCF7 xenograft-bearing mice. In addition, periodic MF cycles were as effective as the CDK4/6 inhibitor, palbociclib, in delaying fulvestrant resistance. … The combination of fulvestrant, MF and palbociclib achieved powerful and long-lasting regression of MCF7 BC cell xenografts, and MF cycles could also reverse acquired resistance to the fulvestrant plus palbociclib regimen [ 58 ]. …

Second-Generation Antimitotics in Cancer Clinical Trials.

Mitosis represents a promising target to block cancer cell proliferation. Classical antimitotics, mainly microtubule-targeting agents (MTAs), such as taxanes and vinca alkaloids, are amongst the most successful anticancer drugs. By disrupting microtubules, they activate the spindle assembly checkpoint (SAC), which induces a prolonged delay in mitosis, expected to induce cell death. However, resistance, toxicity, and slippage limit the MTA's effectiveness. With the desire to overcome some of the MTA's limitations, mitotic and SAC components have attracted great interest as promising microtubule

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… Ongoing | Advanced Nonhematologic Malignancies | Combination with Paclitaxel | - | - CFI-402257 | NCT03568422 | Phase I Phase II Recruiting | Breast Cancer | Combination with Paclitaxel | - | - NCT02792465 | Phase I, Recruiting | Breast Cancer, Advanced Solid Malignancies | Monotherapy Combination with Fulvestrant … Currently, two phase I/II trials are recruiting participants: one for the treatment of advanced solid tumors, including breast cancer, as a monotherapy and in combination with Fulvestrant ( NCT02792465 ), and one in combination with Paclitaxel for breast cancer ( NCT03568422 ). …

Leptomeningeal Disease as an Initial Presenting Manifestation in Breast Cancer.

Leptomeningeal disease (LMD) occurs in less than 5% of breast cancer patients. Rarely, patients present with LMD at diagnosis. We report a case of a 59-year-old female who presented with lower back pain, radicular neuropathy with lower extremity weakness, and was found to have diffuse LMD. Workup was initiated to evaluate the etiology of LMD and later involved iliac bone biopsy showed metastatic adenocarcinoma consistent with breast carcinoma. Patient received radiation therapy followed by abemaciclib with letrozole and responded well with the treatment.

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… The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial. Sledge GW Jr, Toi M, Neven P, et al. …

Polypharmacology: new drugs in 2023-2024.

Polypharmacology is an emerging approach to drug design and development that involves the use of multi-target-directed ligands (MTDLs), agents capable of interacting with multiple biological targets simultaneously. The effective treatment of chronic and multifactorial conditions, driven by the dysregulation of multiple interconnected pathways, such as cancer, autoimmune and metabolic disorders, cardiovascular and neurodegenerative diseases, is one of the most substantial challenges in contemporary pharmacology. 'Traditional' single-target-based treatment frequently shows limited effectiveness,

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… kinase inhibitor | (-) AKT1 (-) AKT2 (-) AKT3 | estrogen receptor-positive, HER2/neu-negative locally advanced or metastatic breast cancer in adult patients with one or more PIK3CA/AKT1/PTEN-alterations following recurrence or progression on or after an endocrine-based regimen (in combination with fulvestrant … In a randomized double-blind clinical trial, co-therapy of capivasertib and the estrogen receptor antagonist fulvestrant resulted in a longer progression-free survival than the administration of fulvestrant alone; this held true for patients with hormone receptor-positive advanced breast cancer when …

Risk Factors for Medication-Related Osteonecrosis of the Jaw-A Binomial Analysis of Data of Cancer Patients from Craiova and Constanta Treated with Zoledronic Acid.

MRONJ (Medication-Related Osteonecrosis of the Jaw) is a condition observed in a subset of cancer patients who have undergone treatment with zoledronic acid in order to either prevent or treat bone metastases. The primary aim of this research was to establish the importance of risk factors in the development of medication-related osteonecrosis of the jaw in cancer patients receiving zoledronic acid therapy for bone metastases. The present study is an observational retrospective investigation conducted at two university centers, namely, Craiova and Constanța, and included cancer patients treate

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… ) PACLITAXEL NAVELBIN CYCLOPHOSPHAMIDE CARBOPLATIN ETOPOSID MELPHALAN (ALKERAN) GEMCITABINE (GEMZAR) DOXORUBICIN COMBINATION CHEMOTHERAPY | EC (EPIRUBICIN, CYCLOPHOSPHAMIDE) PACLITAXEL + NAVELBINE DOXORUBICIN + CYCLOPHOSPHAMIDE ENDOCRINE THERAPY | GOSERELIN (ZOLADEX) ABIRATERON LETROZOLE RIBOCICLIB FULVESTRANT … PALBOCICLIB + FULVESTRANT PALBOCICLIB + LETROZOLE AHT | ATEZOLIZUMAB PEMBROLIZUMAB Author Contributions Conceptualization, G.A.C., D.V., R.M. and S.M.P.; methodology, G.A.C., I.E.S., C.V.L., C.M.M. and S.M.P.; software, M.I., M.I.G., E.C.S. and L.C.; validation, A.C., R.M. and D.V.; formal analysis …

Abstracts of the 28th Annual San Antonio Breast Cancer Symposium, December 8-11, 2005, San Antonio, Texas, USA.

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The PI3K inhibitor buparlisib suppresses osteoclast formation and tumour cell growth in bone metastasis of lung cancer, as evidenced by multimodality molecular imaging.

Non‑small cell lung cancer (NSCLC) metastasis commonly occurs in bone, which often results in pathological fractures. Sustained phosphoinositide‑3‑kinase (PI3K) signalling promotes the growth of PI3K‑dependent NSCLC and elevates osteoclastogenic potential. The present study investigated the effects of a PI3K inhibitor on NSCLC growth in bone and osteoclast formation, and aimed to determine whether it could control symptoms associated with bone metastasis. A bone metastasis xenograft model was established by implanting NCI‑H460‑luc2 lung cancer cells, which contain a phosphatidylinositol‑​4,5‑b

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… J Bleckmann A Beißbarth T Salinas G Riemenschneider MJ PI3K: A master regulator of brain metastasis-promoting macrophages/microglia Glia 66 2438 2455 2018 10.1002/glia.23485 30357946 31 Campone M Im SA Iwata H Clemons M Ito Y Awada A Chia S Jagiełło-Gruszfeld A Pistilli B Tseng LM Buparlisib plus fulvestrant … versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: Overall survival results from BELLE-2 Eur J Cancer 103 147 154 2018 10.1016/j.ejca.2018.08.002 30241001 32 Gdowski AS Ranjan A Vishwanatha JK Current …

Symptom burden and symptom clusters in patients with breast cancer undergoing endocrine therapy: a cross‐sectional survey

OBJECTIVE: In China, many breast cancer (BC) patients opt for traditional Chinese medicine (TCM) to manage unpleasant symptoms. This study aimed to investigate the symptom clusters among patients with BC who are undergoing endocrine therapy and actively seek TCM treatment in China. METHODS: Patients with BC who were undergoing endocrine therapy were recruited. Data on symptom burden were gathered using the M.D. Anderson Symptom Inventory-Traditional Chinese Medicine (MDASI-TCM) and a BC-specific symptom questionnaire. The patient's quality of life (QoL) over the previous week was assessed usi

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… . (%) OFS+AI | 49 (22.9) OFS+SERMs | 14 (6.5) OFS+fulvestrant | 3 (1.4) AI | 80 (37.4) SERMs | 61 (28.5) Fulvestrant | 7 (3.3) Combination treatment, n (%) None | 163 (76.2) Yes | 51 (23.8) CDK4/6 inhibitor | 29 (13.6) HER2-targeted therapy | 16 (7.5) Radiation therapy | 2 (0.9) Bone-modifying agents …

Lack of correlation between the costs of anticancer drugs and clinical benefits in Japan.

Both overall survival (OS) and progression-free survival (PFS) are primary endpoints of phase III studies of new anticancer drugs. Medical care expenditures, especially oncology drug prices, are rapidly increasing; however, the impact of oncology drug prices on OS and PFS is unclear. We analyzed the relationship between oncology drug prices and clinical outcomes in Japan. The costs of a full course or 1 year of treatment were estimated on the basis of the latest National Health Insurance Drug Price Standards, and the relationship between costs and improvements in OS or PFS obtained with each d

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… Erlotinib | NSCLC | 12 240 Sunitinib | RCC | 37 856 | Enzalutamide | PrC | 16 283 Trabectedin | STS | 22 594 | Cetuximab | CRC | 33 474 Pazopanib | STS | 25 406 | Sorafenib | HCC | 37 868 Panitumumab | CRC | 70 687 | Trastuzumab | GC | 24 427 Panobinostat | MuMy | 101 450 | Temsirolimus | RCC | 25 824 Fulvestrant …

Decoding the epitranscriptome: a new frontier for cancer therapy and drug resistance.

As the role of RNA modification in gene expression regulation and human diseases, the "epitranscriptome" has been shown to be an important player in regulating many physiological and pathological processes. Meanwhile, the phenomenon of cancer drug resistance is becoming more and more frequent, especially in the case of cancer chemotherapy resistance. In recent years, research on relationship between post-transcriptional modification and cancer including drug resistance has become a hot topic, especially the methylation of the sixth nitrogen site of RNA adenosine-m6A (N6-methyladenosine). m6A m

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… , Tamoxifen [ 136 ] miR-29a-3p miR-29b-3p miR-222-3p ↓ ↑ BC Fulvestrant, 4-hydroxytamoxifen [ 137 ] ATG4B ↓ ↑ BC Olaparib [ 138 ] NEAT1 ↑ ↑ GC 5-fluorouracil [ 139 ] FOXM1, LCN2 ↑ ↑ EC Cisplatin [ 140 ] AML acute myeloid leukemia, BC breast cancer, CML chronic myeloid leukemia, CRC colorectal cancer … Overexpressing HNRNPA2B1 in MCF-7 cells resulted in drug resistance to TAM and fulvestrant (an antagonist of estrogen receptor). Meanwhile, knockdown of HNRNPA2B1 in LCC9 and LY2 cells restored TAM and fulvestrant, endocrine-sensitivity [ 136 ]. …

Chemotherapy Treatment Modifications During the COVID-19 Outbreak at a Community Cancer Center in New York City.

PurposeAs a result of their immunocompromised status associated with disease and treatment, patients with cancer face a profound threat for higher rates of complications and mortality if they contract the coronavirus disease 2019 infection. Medical oncology communities have developed treatment modifications to balance the risk of contracting the virus with the benefit of improving cancer-related outcomes.MethodsWe systemically examined our community cancer center database to display patterns of change and to unveil factors that have been considered with each decision. We studied a cohort of 28

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… Endocrine therapy included luteinizing hormone–releasing hormone agonists, fulvestrant, tamoxifen, and aromatase inhibitors. Bone-modulatory therapies included zoledronic acid and denosumab. Benign hematology treatments included intravenous iron replacement, erythropoietin, and romiplostim. …

Staying Abreast of New Biomarkers in Hematology/Oncology.

There has been an increasing number of approvals for targeted therapies in oncology in the past decade, changing the treatment paradigm for many solid tumors and hematologic malignancies. At JADPRO Live 2023, presenters provided an in-depth review of cancer biomarkers, including testing methodology, recommended therapies, and how advanced practitioners can integrate results into clinical decision-making.

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… In the EMERALD trial, elacestrant (an oral selective ER degrader that binds to ERα) was compared with standard-of-care endocrine monotherapy (fulvestrant, anastrozole, letrozole, or exemestane). …

Minimal residual disease in solid tumors: Clinical applications and future directions.

Minimal residual disease (MRD) refers to the presence of residual cancer cells or tumor-derived fragments that persist after treatment and remain undetectable by conventional imaging or protein-based assays. Circulating tumor DNA (ctDNA) has emerged as a dynamic biomarker for MRD detection. It enables real-time disease monitoring, prognostication, and often therapeutic decision-making. Two major ctDNA approaches exist, tumor-informed and tumor-agnostic, and they differ in sensitivity, specificity, and clinical feasibility. Recent clinical trials have supported a prognostic and predictive utili

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… | Signatera | Evaluates ctDNA‐guided adjuvant therapy in high‐risk patients | High sensitivity and negative predictive value of test TRAK‐ER | NCT04985266 | ER+/HER2− breast cancer | 2 | NA | Investigates early detection of molecular relapse using ctDNA tracking and treatment with palbociclib plus fulvestrant … | Signatera | Evaluates ctDNA‐guided adjuvant therapy in high‐risk patients | High sensitivity and negative predictive value of test TRAK‐ER | NCT04985266 | ER+/HER2− breast cancer | 2 | NA | Investigates early detection of molecular relapse using ctDNA tracking and treatment with palbociclib plus fulvestrant …

Stage-specific biomarkers in triple-negative breast cancer: Preliminary findings from bioinformatics approaches.

BackgroundIntegrated bioinformatics approaches were used to identify stage-specific candidate genes and potential drug targets in triple-negative breast cancer (TNBC).MethodsMicroarray (164 early-stage, 33 advanced-stage, and 53 normal samples) and RNA-seq (113 normal, 163 early-stage, and 30 advanced-stage TNBC samples) datasets were analyzed. Differentially expressed genes (DEGs) were identified, followed by co-expression analysis using Weighted Gene Co-expression Network Analysis (WGCNA) and protein-protein interaction analysis using the STRING database. miRNA co-regulation was evaluated us

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… Anti-seizures Radiation sensitizer NCAPD2 | Doxorubicin Palbociclib | Calcitriol Cyclosporine Dasatinib Ivermectin Valproic Acid Leflunomide Sunitinib | Anti-hyperparathyroidism Anti-hyperparathyroidism Anti-cancer Anti-worm infection Anti-seizures Anti-rheumatoid arthritis Anti-cancer Advanced | | | F11R | Fulvestrant … Conventional therapies have been identified for some of these genes, such as fulvestrant for F11R, 55 while others ( FOXO6, TMEM51 , and PPP4C ) lack targeted conventional drugs, underscoring the need for further research ( Table 5 ). …

Medicinal chemistry perspectives on anticancer drug design based on clinical applications (2015-2025).

Cancer therapy has undergone a remarkable evolution over the past few decades, driven largely by innovations in medicinal chemistry. This review explores the pivotal role of medicinal chemistry in designing, optimizing, and classifying anticancer agents, from traditional cytotoxics to modern targeted therapies, immunotherapies, and radiotheranostics. The article categorizes FDA-approved anticancer drugs (2015-2025), evaluates their mechanisms of action, structural features, and structure-activity relationships (SAR), and highlights both success stories and challenges in clinical translation. A

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… ensures controlled release within the tumor microenvironment. 54 These innovations enhance therapeutic efficacy while minimizing off-target effects. 55 Additionally, hormonal therapies remain relevant in hormone-driven cancers. 56 Agents such as tamoxifen (a selective estrogen receptor modulator) and fulvestrant … progression from G1 to S phase, and their inhibition by palbociclib results in hypophosphorylation of the retinoblastoma (Rb) protein, cell cycle arrest, and decreased tumor cell proliferation. 90 Palbociclib has a favorable safety profile and is commonly used with endocrine therapy such as letrozole or fulvestrant …

FDA-Approved Small Molecule Compounds as Drugs for Solid Cancers from Early 2011 to the End of 2021.

Solid cancers are the most common types of cancers diagnosed globally and comprise a large number of deaths each year. The main challenge currently in drug development for tumors raised from solid organs is to find more selective compounds, which exploit specific molecular targets. In this work, the small molecule drugs registered by the Food and Drug Administration (FDA) for solid cancers treatment between 2011 and 2022 were identified and analyzed by investigating a type of therapy they are used for, as well as their structures and mechanisms of action. On average, 4 new small molecule agent

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… The approval of abemaciclib (as VERZENIO) includes using it for monotherapy or in combination with fulvestrant, which is an estrogen receptor antagonist. Palbociclib (as IBRANCE) was registered for combination therapy with fulvestrant or an aromatase inhibitor ( letrozole ). … The approval of alpelisib (as PIQRAY) was obtained for usage in combination with an estrogen receptor antagonist ( fulvestrant ) for the treatment of postmenopausal women and men with HR-positive, HER2-negative, advanced or metastatic breast cancer [ 158 ]. …

Translational horizons in the tumor microenvironment: harnessing breakthroughs and targeting cures.

Chemotherapy and targeted therapy have opened new avenues in clinical oncology. However, there is a lack of response in a substantial percentage of cancer patients and diseases frequently relapse in those who even initially respond. Resistance is, at present, the major barrier to conquering cancer, the most lethal age-related pathology. Identification of mechanisms underlying resistance and development of effective strategies to circumvent treatment pitfalls thereby improving clinical outcomes remain overarching tasks for scientists and clinicians. Growing bodies of data indicate that stromal

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… In MCF-7 and T47D breast cancer cells, the acquisition of fulvestrant resistance was accompanied by an increase in c-Met expression, which promoted the response to CAF-secreted HGF. 76 In TNBCs, CAF-released HGF improves survival of breast cancer cells in the presence of EGFR inhibitors gefitinib and … Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: Implications for tumour-stroma interactions. Endocr Relat Cancer. 2006;13(4):1085–1099. doi: 10.1677/erc.1.01270. 77. Mueller KL, Madden JM, Zoratti GL, Kuperwasser C, List K, Boerner JL. …