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Targeting Oncoproteins for Molecular Cancer Therapy

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… Lapatinib-resistance clones were generated by chronic exposure of cancer cell lines and were enriched in androgen receptor signaling events, suggesting the importance of this signaling in lapatinib response [ 81 ]. … In agreement with lapatinib and trastuzumab combinatorial preclinical data, PFS was significantly prolonged in trastuzumab-resistant Her2 + metastatic breast cancer with the combination of trastuzumab and lapatinib [ 105 ]. …

Innovations in chemotherapy and radiation therapy: Implications and opportunities for the Asia-Pacific Rim.

New cases of invasive cancer in the United States occur among nearly 1.5 million people annually. In 2007, more than 1,500 people died per day with this diagnosis. Cancer is responsible for nearly one in every four deaths reported in the country. Enormous amounts of money and research have been, and are being spent, in an attempt to improve these numbers. While prevention and early detection remain the key to long-term success, treatment in the neo-adjuvant, adjuvant and metastatic settings still centre around two main treatment modalities - radiation therapy and chemotherapy. This article wil

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… Phase I data on the combination of trastuzumab and lapatinib has recently been published [ 51 ]. … O’Shaughnessy et al . conducted the first Phase III randomised open-labeled, multi-centered study evaluating lapatinib versus lapatinib + trastuzumab in heavily pre-treated women with HER2+ metastatic breast cancer. …

Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy.

The present studies focused on defining the mechanisms by which anoikis-resistant (AR) mammary carcinoma cells can be reverted to a therapy-sensitive phenotype. AR mammary carcinoma cells had reduced expression of the toxic BH3 domain proteins BAX, BAK, NOXA, and PUMA. In AR cells expression of the protective BCL-2 family proteins BCL-XL and MCL-1 was increased. AR cells were resistant to cell killing by multiple anti-tumor cell therapies, including ERBB1/2 inhibitor + MCL-1 inhibitor treatment, and had a reduced autophagic flux response to these therapies, despite similarly exhibiting increas

Cardiotoxicity of Biological Therapies in Cancer Patients: An In-depth Review.

Cardiotoxicity from chemotherapy regimens has been long reported. However, the understanding of cardiac side effects of biological therapies is rapidly evolving. With cancer patients achieving higher life expectancy due to the use of personalized medicine and novel targeted anticancer agents, the occurrence of cardiotoxicity is becoming more significant. Novel biological therapies include anti-HER2 antibodies, tyrosine kinase inhibitors, bruton kinase inhibitors, antivascular endothelial growth factors, proteasome inhibitors, immunomodulator drugs, and immune checkpoint inhibitors. Potential c

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… Lapatinib Lapatinib is an oral reversible dual tyrosine kinase inhibitor that targets both the epidermal growth factor receptor (EGFR) and HER2, used in the treatment of HER2 positive metastatic breast cancer [ 56 ]. … the lapatinib and capecitabine group [ 60 ]. …

Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer.

The HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for the treatment of metastatic, HER2-positive breast cancer after prior trastuzumab and taxane therapy, and has also demonstrated efficacy in the adjuvant setting in incomplete responders to neoadjuvant therapy. Despite its objective activity, intrinsic and acquired resistance to T-DM1 remains a major clinical challenge. T-DM1 mediates its activity in a number of ways, encompassing HER2 signalling blockade, Fc-mediated immune response and payload-mediated microtubule poisoning. Resistance mechanisms relating t

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… Junttila TT Li G Parsons K Phillips GL Sliwkowski MX Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer Breast Cancer Res. Treat 2011 128 347 356 10.1007/s10549-010-1090-x 20730488 19. … Loibl S Majewski I Guarneri V Nekljudova V Holmes E Bria E PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab Ann. …

Clinical development of targeted and immune based anti-cancer therapies.

Cancer is currently the second leading cause of death globally and is expected to be responsible for approximately 9.6 million deaths in 2018. With an unprecedented understanding of the molecular pathways that drive the development and progression of human cancers, novel targeted therapies have become an exciting new development for anti-cancer medicine. These targeted therapies, also known as biologic therapies, have become a major modality of medical treatment, by acting to block the growth of cancer cells by specifically targeting molecules required for cell growth and tumorigenesis. Due to

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… (Tykerb®) Lapatinib (1250 mg/d) + capecitabine (2000 mg/m 2 ) NCT00078572 Breast (HER2+) Capecitabine 2004–2006 GSK III 408 17.3 vs 14.9 7.2 vs 4.3 Lapatinib (1500 mg/d) + letrozole (2.5 mg/d) NCT00073528 Breast (ER/PR +) Letrozole 2003–2018 Norvatis III 1285 33.3 vs 32.3 8.1 vs 3.0 Lapatinib (1500 … (Tykerb®) Lapatinib (1250 mg/d) + capecitabine NCT00078572 Metastatic breast cancer (HER2+) Capecitabine 2004–2010 GSK III 408 10.4 vs 8.0 8.4 vs 4.4 Lapatinib (1500 mg/d) NCT00073528 Metastatic breast cancer Letrozole 2003–2018 Novartis III 1285 33.3 vs 32.3 8.1 vs 3.0 Lapatinib (1500 mg/d) NCT00374322 …

Getting to the Heart of the Matter: An Overview of Cardiac Toxicity Related to Cancer Therapy.

With the improvement in cancer survival, long-term cardiotoxicity has become an area of increased interest. Various cancer therapies, including chemotherapy and radiation therapy can lead to cardiac toxicities with both acute and chronic manifestations. Awareness and early recognition can lead to improvement in cardiac survival and patient outcomes. The focus of this review is to summarize the cancer therapy agents most often associated with cardiovascular side effects, highlighting their mechanism of action and strategies for surveillance and prevention.

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… cells, resulting in a decrease in circulating lymphocytes. 32 This agent has been shown to cause an acute myopericarditis as well as LVD in 7%–22% of patients that is thought to be dose related. 4 , 33 – 35 Small tyrosine kinase inhibitors Tyrosine kinase inhibitors such as sunitinib, imatinib, and lapatinib … , which inhibits both ErbB1 and ErbB2, has been shown to cause QT prolongation in addition to reduced LVEF in 1.6% of patients. 7 In contrast to trastuzumab, another inhibitor or ErbB2, lapatinib is less car-diotoxic. 38 Because hypertension is a common effect observed with agents that interfere with …

Prioritising systemic cancer therapies applying ESMO's tools and other resources to assist in improving cancer care globally: the Kazakh experience.

BackgroundIn Kazakhstan, cancer is the second leading cause of death with a major public health and economic burden. In the last decade, cancer care and cancer medicine costs have significantly increased. To improve the efficiency and efficacy of cancer care expenditure and planning, the Kazakhstan Ministry of Health requested assistance from the World Health Organization (WHO) and the European Society for Medical Oncology (ESMO) to review its systemic cancer treatment protocols and essential medicines list and identify high-impact, effective regimens.Materials and methodsESMO developed a four

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… Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer J Clin Oncol 28 2010 1124 1130 20124187 10.1200/JCO.2008.21.4437 18 Cristofanilli M. Turner N.C. Bondarenko I. … Lapatinib plus capecitabine for HER2-positive advanced breast cancer N Engl J Med 55 2006 2733 2743 10.1056/NEJMoa064320 17192538 25 Miller K. Wang M. Gralow J. …

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13.

Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe.Design Retrospective cohort study.Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013.Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after marke

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… Similarly, the pivotal trial to support lapatinib in combination with trastuzumab for patients with metastatic breast cancer used lapatinib monotherapy as the comparison—a treatment acknowledged in the EPAR to be “without established efficacy.” 86 Although this trial design failed to isolate the effects … combined with tratuzumab, the pivotal study was scored 4 on the basis of a 4.5 month survival gain over lapatinib monotherapy (with no established efficacy). …

Navigating antibody‒drug conjugates (ADCs): from metastatic to early breast cancer treatment strategies.

We are currently living in the era of precision medicine, and antibody‒drug conjugates (ADCs) represent promising advancements in targeted cancer therapy. While several ADCs have been investigated over the years, only three have gained FDA approval for breast cancer (BC): ado-trastuzumab emtansine (T-DM1/Kadcyla), trastuzumab deruxtecan (T-DXd/Enhertu), and sacituzumab govitecan (SG/Trodelvy). This review focuses on the three approved ADCs for BC, reviewing the trials that led to their approval and detailing the ongoing trials testing their clinical efficacy and safety profiles. We examine ong

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… + capecitabine: 6.2 | | | Lapatinib + capecitabine | mOS % (HR 0.68) T-DM1: 30.9% Lapatinib + capecitabine: 25.1% KATHERINE Study (2019) [ 12 ] | III | Adjuvant setting for residual invasive HER2 + early BC after neoadjuvant chemotherapy and HER2-targeted therapy | T-DM1 | OS rate %: (HR 0.66) T-DM1 … Finally, TAA013 is a phase III trial comparing TAA013 with lapatinib combined with capecitabine in HER2 + BC [ 160 ]. …

Arrhythmias, conduction disorders and sudden cardiac death in cancer patients and survivors: expert opinion of the working groups on cardio-oncology and on electrophysiology of the hellenic cardiac society.

Advances in cancer therapeutics have significantly improved patient survival; however, cardiotoxic effects-including arrhythmias-have emerged as a growing clinical concern. This expert opinion, developed by the Working Groups on Cardio-Oncology and Electrophysiology of the Hellenic Cardiological Society, aims to raise awareness of the increasing burden of arrhythmias in cancer patients and survivors. This document explores the multifactorial etiology of arrhythmias in this population, including patient-related factors, the direct effects of malignancy, and the arrhythmogenic potential of thera

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… nilotinib, ponatinib) BRAF inhibitor (dabrafenib, encorafenib, vemurafenib) BTK inhibitor (acalabrutinib, ibrutinib) c-MET inhibitor (cabozantinib) CDK inhibitor (abemaciclib, palbociclib, ribociclib) EGFR/VEGF TKI (vandetanib, axitinib, pazopanib, regorafenib, sorafenib, sunitinib, erlotinib, gefitinib, lapatinib … EGFR/VEGF TKI (vandetanib, axitinib, pazopanib, regorafenib, sorafenib, sunitinib, erlotinib, gefitinib, lapatinib, neratinib, osimertinib) FLT3 inhibitor (gilteritinib) HDAC inhibitor (panobinostat) Hedgehog pathway inhibitor (glasdegib, sonidegib) IDH1 inhibitor (ivosidenib) MEK inhibitor (cobimetinib …

Relative value assessment: characterizing the benefit of oncology therapies through diverse survival metrics from a US perspective.

ObjectivesThe introduction of innovative, high-cost oncology treatments, coupled with mounting budgetary pressures, necessitates value trade-offs across cancer types. Defining value is critical to informing decision-making. A cost-value analysis tool was used to assess relative clinical value from a US perspective using multiple outcome metrics for a variety of metastatic cancers.MethodsLiterature published (January 1, 2000-August 31, 2016) was reviewed to identify outcome metrics for approved treatments for metastatic cancers. Data were extracted or derived for median and mean overall surviva

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… + capecitabine Pertuzumab + trastuzumab + docetaxel 110 – 114 | NA | 1L | CLEOPATRA | Placebo + trastuzumab + docetaxel Trastuzumab emtansine + placebo 115 | NA | 1L | MARIANNE | Trastuzumab + taxane (docetaxel/paclitaxel) Lapatinib 116 , 117 | NA | 1L | EGF 30008 | Letrozole + placebo Lapatinib + capecitabine … advanced breast cancer: final survival analysis of a phase III randomized trial Oncologist 2010 15 9 924 934 20736298 10.1634/theoncologist.2009-0181 PMC3228041 120 Assessment report for Tykerb (lapatinib). …

Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention.

The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstre

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… The HRG siRNA synergized with the HER2 inhibitors herceptin (trastuzumab) and lapatinib. Treatment of the cells with a PI3K inhibitor (BEZ235) suppressed HRG and P-AKT levels. When the cells were cotreated with BEZ235 and lapatinib, a complete suppression of growth was observed. … However, co-inhibition of PI3K with the PI3K-alpha specific inhibitor BYL719 and EGFR-mediated signaling with lapatinib was more effective in suppressing growth than treatment with either the PI3K-alpha inhibitor or lapatinib alone. …

Availability, price and affordability of anticancer medicines in Jiangsu Province, China: a cross-sectional survey study.

BackgroundTo evaluate anticancer medicines' availability, price and affordability in nine prefecture-level cities, Jiangsu Province.MethodsBased on the standard methods recommended by the World Health Organization (WHO) and the Health Action International (HAI), a cross-sectional survey was performed to collect information about 24 essential anticancer medicines (EAMs) and 17 innovative anticancer medicines (IAMs) in hospitals and 45 community pharmacies in Jiangsu Province from July to November 2021.ResultsIn general, the availability of EAMs during the study period was higher than that of IA

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… Only one new antitumor drug is available> 50% in community pharmacies, two in medical institutions, and only one variety with relatively good affordability in community pharmacies, lapatinib. … Among the 17 novel anticancer drugs assessed in this study, only lapatinib failed to renew its agreement in 2019; the remaining drugs were either included in the national negotiation catalog or directly incorporated into the standard reimbursement list. …

Safety and Tolerability of Antibody-Drug Conjugates in Cancer.

Antibody-drug conjugates are monoclonal antibodies attached to biologically active drugs through chemical linkers that deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. Currently, there are about 110 ongoing studies implementing antibody-drug conjugates in the treatment of multiple human malignancies. Antibody-drug conjugates carry a feature of the specificity of a monoclonal antibody and the anti-neoplastic potential of a cytotoxin. The first antibody-drug conjugate was approved in 2001, and the field of antibody-drug

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… Thrombocytopenia after T-DM1 was found in up to 31.2% of patients, compared with 3.3% in the lapatinib plus capecitabine group. [ 46 ] Grade ≥ 3 low platelet count was reported in 14.5% of patients receiving T-DM1, and 0.4% receiving lapatinib plus capecitabine. … Peripheral neuropathy was reported in 21.1% of patients taking T-DM1 and 13.5% in the lapatinib plus capecitabine-treated group. [ 46 ] The incidence of grade ≥ 3 PN was 2.2% in the T-DM1-treated group and 0.2% in the lapatinib plus capecitabine-treated group. …

Ferroptosis: Frenemy of Radiotherapy.

Recently, it was established that ferroptosis, a type of iron-dependent regulated cell death, plays a prominent role in radiotherapy-triggered cell death. Accordingly, ferroptosis inducers attracted a lot of interest as potential radio-synergizing drugs, ultimately enhancing radioresponses and patient outcomes. Nevertheless, the tumor microenvironment seems to have a major impact on ferroptosis induction. The influence of hypoxic conditions is an area of interest, as it remains the principal hurdle in the field of radiotherapy. In this review, we focus on the implications of hypoxic conditions

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… Ferroptosis induction following lapatinib in combination with siramesine or a single treatment with neratinib has been described in diverse cancer types ( Figure 2 ) [ 129 , 130 , 131 ]. The radiomodulatory properties of Lapatinib were first described in 2010. … HER2+ and EGFR+ breast cancer cells were radiosensitized using lapatinib in a fractionated radiation treatment regimen. However, the exact underlying mechanism was not unraveled [ 132 ]. Lapatinib was confirmed to be a radiosensitizer in two different breast cancer cell lines. …

'The same old story': thoughts on authorized doses of anticancer drugs.

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… Lapatinib plus Capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355: 2733–2743. 11. Devriese LA, Koch KM, Mergui-Roelvink M, et al. Effects of low-fat and high-fat meals on steady-state pharmacokinetics of lapatinib in patients with advanced solid tumours. … The value meal: how to save $1700 per month or more on Lapatinib. J Clin Oncol 2007; 25: 3397–3398. 13. Grothey A, Van Cutsem E, Sobrero A, et al. …

An overview of antibody-drug conjugates in oncological practice.

Antibody-drug conjugates (ADCs) are designed to manipulate the toxic efficacy of specific chemotherapeutic compounds, employing the high affinity of antibody-mediated delivery so as to drive them selectively to target cancer cells. These immunoconjugates encompass the general tendency towards precision medicine and avert the systemic toxicities of conventional chemotherapy, accomplishing an improved therapeutic index. Cumulative experience acquired from first-generation ADCs offers new perspectives to these promising therapeutic modalities for various hematological and solid cancers and propel

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… Mol Biol Int 2014 ; 2014 : 852748 . 25276427 10.1155/2014/852748 PMC4170925 40 Junttila TT Li G Parsons K , et al Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer . … Ann Oncol 2015 ; 26 : 113 – 119 . 25355722 10.1093/annonc/mdu486 PMC4679405 44 Dieras V Miles D Verma S , et al Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival …

An Appraisal of the Oleocanthal-Rich Extra Virgin Olive Oil (EVOO) and Its Potential Anticancer and Neuroprotective Properties.

Dietary consumption of olive oil represents a key pillar of the Mediterranean diet, which has been shown to exert beneficial effects on human health, such as the prevention of chronic non-communicable diseases like cancers and neurodegenerative diseases, among others. These health benefits are partly mediated by the high-quality extra virgin olive oil (EVOO), which is produced mostly in Mediterranean countries and is directly made from olives, the fruit of the olive tree (Olea europaea L.). Preclinical evidence supports the existence of antioxidant and anti-inflammatory properties exerted by t

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… EGFR (Epidermal growth factor receptor), HER2 and c-Met receptor activation, as compared to oleocanthal monotherapy or lapatinib monotherapy. … Authors also reported the inhibition of tumor recurrence by oleocanthal after the completion of neoadjuvant treatment with lapatinib (50 mg/kg; oral, 5X/week, for 19 days). …

Clinical trial challenges, design considerations, and outcome measures in rare CNS tumors.

Clinical research for patients with rare cancers has been very challenging. First and foremost, patient accrual to clinical trials typically requires a network, cooperative group, or even international collaboration in order to achieve the necessary numbers of patients to adequately evaluate a new treatment or intervention. Similar limitations in preclinical models and in the understanding the natural history of the disease or pertinent prognostic factors further impede the development of hypothesis-based, appropriately powered clinical trials. However, despite these challenges, several studie

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… Fig. 3 Comparison of incidence of moderate-to-severe spine symptoms from baseline to cycle 6 of temozolomide-lapatinib treatment (negative change means fewer patients). … A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma. Neuro Oncol. 2021;23(3):468–477. 14. Jürgensmeier JM, Eder JP, Herbst RS. …