Development of Second-Generation VEGFR Tyrosine Kinase Inhibitors: Current Status

The vascular endothelial growth factor (VEGF) signaling pathway appears to be the dominant pathway involved in tumor angiogenesis, providing a rationale for targeting the VEGF receptors (VEGFR-1, -2, and -3) in the treatment of cancers. In particular, VEGF signaling is thought to be important in renal cell carcinoma (RCC) because of the deregulation of the pathway through nearly uniform loss of the von Hippel Lindau protein. The tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib are approved by the US Food and Drug Administration for the treatment of advanced RCC; however, these multitargeted agents inhibit a wide range of kinase targets in addition to the VEGFRs, resulting in a range of adverse effects unrelated to efficient VEGF blockade. This article reviews recent advances in the development of the second-generation VEGFR TKIs, including the more selective VEGFR TKIs tivozanib and axitinib, and focuses on the potential benefits of novel inhibitors with improved potency and selectivity.     

酪氨酸激酶抑制剂在抗肿瘤领域的研究进展

酪氨酸蛋白激酶是多种肿瘤最常见的生长因子受体，是信号转导过程中的首要关键步骤。通过阻断酪氨酸激酶可破坏肿瘤细胞的信号传递，从而达到治疗肿瘤的目的。近年来，有关酪氨酸激酶抑制剂的研究非常活跃，出现了诸如C225，C11033，PKI-166，OSI-774，ZDl839，STl571等一批新药。OSI-774和ZDl839已使难治性非小细胞肺癌患者的病情减缓。C225可提高化、放疗的疗效，STl571在慢性粒细胞性白血病和胃肠间质性肿瘤治疗中取得了突破性进展。酪氨酸激酶抑制剂已成为抗肿瘤疗法中的一个新的有希望的侯选药物。     

Receptor Tyrosine Kinase Fusions and BRAF Kinase Fusions are Rare but Actionable Resistance Mechanisms to EGFR Tyrosine Kinase Inhibitors

Introduction

We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs).

Tyrosine Kinase Inhibitors and Anti-Angiogenic Therapies in Kidney Cancer

Opinion statements Renal cell carcinoma (RCC) is a heterogeneous disease as reflected in its presentation and clinical course, pathological subtypes, nuclear grades and molecular biology. Emerging data indicate that renal tumors express a variety of molecular tumor markers and unique patterns of gene expression. Clinically the disease behaves quite heterogeneously, with courses ranging from indolent to highly aggressive. Surgical monotherapy or as part of a multimodal approach remains the standard of care for most cases of RCC. Radical or partial nephrectomy is associated with a 5-year cancer specific survival (CSS) of 85–97% for pT1 tumors. Unfortunately, 20% of patients have either locally advanced or node positive (N+) RCC while another 22% have metastatic RCC (mRCC) at presentation. Unlike the outcomes in early localized disease, survival rates for N+ patients are poor and patients with mRCC are rarely cured despite aggressive multimodal therapy. Classic cytotoxic chemotherapy has repeatedly been shown to have little effect and only 5–20% of patients with mRCC respond to immunologic agents such as interferon and/or interleukin. Cytoreductive nephrectomy with systemic immunotherapy is associated with few cures with median survivals of 12–24 months. Recent advances in our understanding of the molecular origins and pathways of RCC have led to the development of more effective targeted therapies. Here we review the molecular pathways that define the pertinent therapeutic targets in RCC and the clinical data for these new and promising agents.     

Cardiotoxicity Monitoring in Patients Treated with Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) can cause cardiotoxicity, and some suggest routine monitoring of cardiac function during TKI use. We describe two cases of TKI-induced heart failure (HF) that suggest the utility of monitoring with laboratory tests is questionable. One patient developed HF 5 days after starting pazopanib. The other developed HF while receiving 25 mg per day sunitinib, and had previously received a higher dose (50 mg per day) with no symptoms of cardiotoxicy. In addition, she later received 5 cycles of sunitinib (25 mg per day) without developing an abnormal left ventricular ejection fraction (LVEF) value by echocardiography or cardiac symptoms. Although the LVEF is commonly performed to monitor TKI cardiotoxicity, evidence for its predictive utility is limited. These cases raise questions regarding the practical utility of sequential measurement of LVEF in adults treated with TKIs. We suggest a simple daily activity such as stair climbing to monitor exercise tolerance.     

Tyrosine Kinase Inhibitors in Ph Chronic Myeloid Leukemia Therapy: a Review

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. Deregulated BCRABL fusion tyrosine kinase activity is the main cause of CML disease pathogenesis, making BCRABL an ideal target for inhibition. Current tyrosine kinase inhibitors (TKIs) designed to inhibit BCRABL oncoprotein activity, have completely transformed the prognosis of CML. Interruption of TKI treatment leads to minimal residual disease reside (MRD), thought to reside in TKIinsensitive leukaemia stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML either as small molecule master TKIs or phytopharmaceuticals derived from nature to achieve chronic molecular remission. This review outlines the past, present and future therapeutic approaches for CML including coverage of relevant mechanisms, whether ABL dependent or independent, and epigenetic factors responsible for developing resistance against TKIs. Appearance of mutant clones along the course of therapy either preexisting or induced due to therapy is still a challenge for the clinician. A proposed invitro model of generating colony forming units from CML stem cells derived from diagnostic samples seems to be achievable in the era of high throughput technology which can take care of single cell genomic profiling.     

Evaluation of Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

The epidermal growth factor system is a well characterized growth factor receptor pathway, the deregulation of which has been be associated with neoplastic growth. Overexpression or amplification of the epidermal growth factor receptor (EGFR) or one of its ligands has been linked with the malignant transformation of cells and is correlated with poor prognosis in patients. PD 153035, a quinazoline, has been shown to inhibit the tyrosine kinase activity of EGFR by blocking ATP binding (Fry et al., Science 265: 1093-1095, 1994). We set out to determine whether the growth inhibition caused by this agent and five related compounds is a direct result of the blocking of EGFR signaling. The effects on cell proliferation produced by these agents were tested on several tumor cell lines and EC50 values obtained. The EGF responsive cell lines A-431 and MDA-MB-468 exhibit EC50 values of 3 and 6.7 micro M, respectively, for PD 153035 which was found to be the most potent. The agents were then tested for their ability to block the paradoxical high dose EGF induced inhibition of A-431 and MDA-MB-468 cell growth as well as EGF induced phosphorylation in A-431 cells. These compounds are able to completely block the effects of exogenously added EGF at 0.5 microM or less. However, higher doses (EC50's >or= 2 microM) were needed to block the growth of human tumor cell lines potentially implicating a second site of action for these compounds.     

Long-Term Side Effects of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Most patients with chronic myeloid leukemia have deep and durable responses when treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs). Imatinib (the first approved TKI), nilotinib, and dasatinib are used in newly diagnosed, relapsed or intolerant patients, while bosutinib and ponatinib are used only in relapsed or intolerant patients. Previously the drug of choice was related to the likelihood of response and, to a small extent, patient comorbidities. The long-term toxicities, particularly cardiopulmonary side effects, are now impacting treatment choice, making patient comorbidities of significant concern. About 10 % of patients do not tolerate their initial BCR-ABL1 TKI and an increasing number are developing long-term side effects, particularly with the second generation drugs. Side effects of the five drugs reviewed here highlight the differences between cardiovascular, pulmonary, gastrointestinal, and endocrine toxicities, as well as possible second malignancies. There is increasing evidence that patients whose disease is controlled by TKI’s will have greater impact on their quality of life from comorbidities or drug adverse events than from the disease itself. Research into management of long-term toxicities is needed.     

Hepatitis B Virus Reactivation in Patients Receiving Bruton Tyrosine Kinase Inhibitors

BackgroundBruton tyrosine kinase (BTK) inhibitors are used to treat B-cell hematologic malignancies. Ibrutinib has been associated with hepatitis B virus (HBV) reactivation. We sought to identify patients with hematologic malignancies who developed HBV reactivation after receiving first-generation (ibrutinib) or second-generation (acalabrutinib and zanubrutinib) BTK inhibitors.MethodsWe retrospectively studied all consecutive patients with hematologic malignancies with past HBV infection (HBV surface antigen [HBsAg] negative and hepatitis B core antibody [anti-HBc] positive) or chronic HBV infection (HBsAg positive and anti-HBc positive) treated with BTK inhibitors at our institution from November 1, 2015, through November 1, 2022.ResultsOf 82 patients initially identified, 53 were excluded (11 because of false-positive anti-HBc results, and 42 because they were receiving anti-HBV prophylaxis owing to recent receipt of anti-CD20 monoclonal antibodies). The 29 remaining patients were further analyzed and 3 (10%; 2/28 with past and 1/1 with chronic HBV infection) were found to have HBV reactivation. One patient received ibrutinib, and 2 received acalabrutinib. All developed HBV-associated hepatitis requiring anti-HBV therapy and survived. One patient continued receiving acalarutinib. Among the patients with past HBV infection, 13 received ibrutinib and 1 (8%) had HBV reactivation; 14 received acalabrutinib and 1 (7%) had HBV reactivation (P = 1.0).ConclusionsHBV reactivation risk is intermediate in patients with past HBV infection who receive BTK inhibitors. For patients with past HBV infection who received BTK inhibitors, data are insufficient to recommend universal anti-HBV prophylaxis, but monitoring for HBV reactivation is warranted.