Treatment options for mantle cell lymphoma

Introduction: In this article, we provide an accurate overview of both standard treatment option and novel promising therapeutics. Major impact is on novel agents now being tested in randomized clinical trials. While the initial data are promising, they may rapidly expand treatment options, change existing paradigms and further improve outcomes for mantle cell lymphoma (MCL) patients.

Areas covered: MCL is a disease with indolent histology, but aggressive clinical course. However, for now, MCL remains incurable and the search for the most effective and tumor-specific treatment still represents a great challenge for oncohematologists. However, the implementation of chemotherapy together with the anti-CD20 antibody rituximab, as well as the growing use of autologous stem cell transplantation in first remission, have improved effects of treatment in MCL, including even some improvement in overall survival. Recently, treatment modalities for MCL have been expanded by strategies based on several biologically targeted agents, including m-TOR kinase or proteasome inhibitors and immunomodulatory agents, such as lenalidomide. B-cell receptor pathway inhibitors, such as ibrutinib and idelalisib, and histone deacetylase or cyclin-dependent kinase inhibitors have also shown promising activity in resistant or relapsed disease.

Expert opinion: Although enormous progress was made in the treatment of MCL over the last year, the disease remains incurable. One chance for the significant life prolongation is intensive treatment with consolidative auto SCT. However, real progress may be afforded by developing the novel agents described in this article. In this way, MCL may soon become another potentially curable oncological malignancy.     

The preclinical discovery and development of dolutegravir for the treatment of HIV

Introduction: Integration of the viral genome into the host cell chromatin is a central step in the replication cycle of HIV. Blocking the viral integrase (IN) enzyme therefore provides an attractive therapeutic strategy, as evidenced by the recent clinical approval of three IN strand transfer inhibitors. Dolutegravir is a therapy that is unique in its ability to evade HIV drug resistance in treatment-naïve patients.

Areas covered: This review starts by providing a brief summary of the history of HIV-1 IN inhibitors. The authors follow this with details of the discovery and preclinical and clinical developments of dolutegravir. Finally, the authors provide details of dolutegravir’s post-launch including the launch of the combination pill of dolutegravir, abacavir and lamivudine in August 2014.

Expert opinion: The launch of raltegravir, the first IN inhibitor from Merck & Co., has created new hopes for the patient. Indeed, pharmaceutical companies have not lost courage by attempting to address the major drawbacks of this first-in-class molecule. And while the drug elvitegravir has been inserted into a four-drug combination pill providing a once-daily dosing alternative, dolutegravir has demonstrated superiority in terms of its efficacy and resistance.     

Lenalidomide for the treatment of mantle cell lymphoma

Introduction: Although a variety of therapeutic schemes for Mantle Cell Lymphoma (MCL) have been attempted, the clinical outcome of patients continues to be unsatisfactory especially among patients with a very high-risk profile and in the relapsed/refractory setting. For this reason, recent clinical trials have explored novel approaches, either by the use of biological agents in chemotherapy-free schedules or by integrating them with chemoimmunotherapy regimens.

Areas covered: The efficacy of lenalidomide monotherapy and combination therapy established in clinical studies mainly involving relapsed/refractory MCL is reviewed. The mechanism of action of lenalidomide is also discussed. Furthermore, the current position of lenalidomide in the MCL treatment algorithm is debated.

Expert opinion: Lenalidomide demonstrated high efficacy and tolerability in several clinical trials as well as in retrospective real-world reports, even in patients who relapsed or were resistant to bortezomib and ibrutinib. In 2013, lenalidomide was approved by the Food and Drug Administration (FDA) for relapsed/refractory MCL after two prior therapies including at least one prior treatment with bortezomib. However, the potential synergistic anti-neoplastic effects of lenalidomide in combination with other biological agents, i.e. ibrutinib and venetoclax, especially in the management of p53-mutated cases, still remain an open issue.     

Acalabrutinib for adults with mantle cell lymphoma

Introduction: Although advances in mantle cell lymphoma (MCL) therapy have improved overall survival (OS), managing relapsed/refractory (R/R) cases remains a great challenge. Bruton tyrosine kinase (BTK) inhibitors have broadened therapeutic options in MCL and became the backbone of second-line strategies.

Areas covered: Ibrutinib, the first-in-class BTK inhibitor registered for MCL therapy, is efficient, with clear benefits of its use. However, ibrutinib-related adverse events due to off-target inhibition of other kinases led to the development of more selective molecules with comparable efficacy and better safety profiles.

Expert commentary: Acalabrutinib, a new BTK inhibitor, currently being evaluated in numerous clinical studies is approved by FDA in relapsing/refractory MCL. Its role will evolve over the next few years. Efficacy and good tolerability of acalabrutinib gives even greater opportunity for potential upfront use and new therapeutic combinations, including monoclonal antibodies, antibody-drug conjugates, immune checkpoint inhibitors, bcl-2 (B-cell lymphoma-2) or IP3K (phosphoinositide 3-kinase) inhibitors.     

Novel therapeutic targets in mantle cell lymphoma

Mantle cell lymphoma (MCL) is characterised by cell cycle dysregulation and a defective DNA damage response pathway. An evolving understanding of these processes has provided the rationale for development of novel agents targeting various steps that appear to be involved in lymphomagenesis and disease progression. Cyclin D1, overexpressed in nearly 100% of MCL, and the cyclin-dependent kinases were among the first rational targets identified. Therapies focusing on the PI3K/Akt pathway, the tumour microenvironment, and cell surface markers are also in various stages of exploration. Here, the authors discuss the rationale for developing targeted therapies and discuss future challenges in combining some of these agents.     

Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence

The ubiquitin–proteasome pathway is the main proteolytic system present in the nucleus and cytoplasm of all eukaryotic cells. Apoptosis activation induced by ubiquitin–proteasome pathway inhibition makes the proteasome a new target of anticancer therapy. Bortezomib is the first proteasome inhibitor to be approved by the US FDA; in 2003 as a third line and in 2005 as a second line therapy for the treatment of multiple myeloma only. This review focuses on the use of bortezomib, not only in its therapeutic role but also, more specifically, in its biologic role and discusses the most recent applications of the drug in solid tumors, both at a preclinical and clinical level.     

帕唑帕尼靶向治疗肾细胞癌的研究进展

帕唑帕尼于2009年10月获美国FDA批准上市用于治疗肾细胞癌,是一种新型的口服多靶点酪氨酸激酶抑制剂。临床研究表明,其对肾细胞癌的药效明显、药动学稳定,安全性研究结果也表明患者耐受良好,该药为晚期肾细胞癌的治疗提供了新的选择。本文就肾细胞癌的发病机制、帕唑帕尼的临床研究和安全性研究及与其他治疗肾细胞癌的酪氨酸激酶抑制剂对比研究进行综述。     

复发/难治性套细胞淋巴瘤治疗进展

套细胞淋巴瘤（MCL）是一种罕见的B细胞恶性肿瘤,占所有非霍奇金淋巴瘤（NHL）的3%~10%,常见于男性,中位发病年龄67岁,具有不可治愈、易复发和耐药等特点,复发后患者预后常较差,治疗选择有限。近年来,随着布鲁顿酪氨酸激酶抑制剂（BTKi）、B细胞淋巴瘤因子2抑制剂（BCL-2i）等为代表的靶向药物的应用,以及嵌合抗原受体T细胞（CAR-T）及异基因干细胞移植（allo-SCT）等疗法的进展,复发难治性（R/R）MCL患者的生存期明显延长。本文拟对目前R/R MCL的治疗进展进行综述。     

Clinical management of mantle cell lymphoma in the elderly

ABSTRACT

Introduction: Mantle cell lymphoma (MCL) is a disease with an indolent histology, but mostly aggressive clinical course. While treatment can yield more promising results in younger patients, the disease is most diagnosed at a median age of approximately 70 years, and treatment in this group still presents a major challenge for oncohematologists. Unfortunately, due to comorbidities and poorer general status, the implementation of intensive treatment approaches with the cytarabine-based regimens and autologous stem cell transplantation is generally not possible, and the disease remains incurable, especially in elderly patients.

Areas covered: In this paper, the authors discuss the therapeutic options available for older patients with MCL in the first line and relapsed/refractory settings, indicating new therapeutic options, which may achieve longer remissions and overall survival.

Expert opinion: Although great progress has been made in the treatment of MCL in recent years, there remains a need for new treatment lines which can allow improved patient outcomes. Novel agents targeting altered the signal transduction pathways in MCL cells may offer more promise than traditional chemotherapy or immunochemotherapy and are currently being tested in clinical trials.     

The preclinical profile of crizotinib for the treatment of non-small-cell lung cancer and other neoplastic disorders

Introduction: The critical role of the activity of the nucleophosmin- anaplastic lymphoma kinase (NPM-ALK) fusion protein in anaplastic large-cell lymphoma prompted drug discovery programs directed against ALK. Drug discovery efforts increased after finding that about 4% of non-small-cell lung cancers (NSCLCs) possess an EML4-ALK fusion protein.

Areas covered: The author provides a review of the development of crizotinib, an orally effective c-Met and ALK protein kinase inhibitor. The article highlights its beginning with the X-ray crystallographic structure of a lead compound (PHA-0665752) bound to the active site of the kinase domain of c-Met.

Expert opinion: Studies of patients with EML4-ALK–positive NSCLC showed that crizotinib was clinically effective and led to its approval in August 2011. The use of lipophilic efficiency played a crucial role in the development of crizotinib from a lead c-Met inhibitor. The use of X-ray crystal structures from lead compounds, bound to their targets, is increasing in the drug discovery process owing to its effectiveness. That the drug also inhibits ALK and ALK-fusion proteins was serendipitous, however. The discovery of the EML4-ALK fusion protein in some NSCLC patients has led to the testing and rapid approval of the compound.     

27 例套细胞淋巴瘤的临床特征及预后分析

目的 探讨套细胞淋巴瘤（MCL）的临床特征、化疗方案的疗效及预后情况。 方法 回顾性分析 27 例 MCL 患者资料, 分析其临床特征及治疗方案, 采用 Cox 回归分析 MCL 预后的影响因素。 结果 27 例患者中位发病年龄为 68 岁, 男女比例为 4.4∶ 1, Ann Arbor 分期Ⅲ～ Ⅳ者 25 例（92.6%）, 肝脾肿大者 8 例（29.6%）, 淋巴结外受累部位＞ 2 者 7 例（25.9%）、 ECOG 评分 2～ 4 分者 4 例（14.8%）, MIPI 评分 0～ 3 分者 8 例（29.6%）、 4～ 5 分者 14 例（51.9%）、6～ 11 分者 5 例（18.5%）, Ki-67≤30%者 9 例（33.3%）, ＞ 30%者 18 例（67.7%）, 有 B 症状者 10 例（37.0%）,乳酸脱氢酶（LDH）值升高者 17 例（63.0%）, β2-微球蛋白值升高者 8 例（29.6%）, 骨髓浸润者 7 例（25.9%）。 R-CHOP 方案组总有效率（ORR）为 81.8%, CHOP 方案组 ORR 为 68.8%。 多因素分析示年龄、LDH、Ki-67 为影响 MCL 预后的独立因素（P＜ 0.05）。 结论 MCL 以晚期多见, 年龄＞ 60 岁、LDH 值升高、Ki-67＞ 30%的患者预后不佳。     

Recent advances in the pharmacological treatment of colorectal cancer

Recent advances in the treatment of colorectal cancer have lead to significant gains in response rates and survival. The combination of newer agents such as irinotecan and oxaliplatin with 5-fluorouracil/leucovorin using various dosing schedules in the metastatic setting has resulted in a steady improvement in the outcome of patients with colorectal cancer. Experimental therapies such as epidermal growth factor receptor inhibitors, vascular endothelial growth factor inhibitors and cyclooxygenase-2 inhibitors, have shown promise in early clinical trials and have acceptable toxicity profiles. Efforts towards improving risk-stratification of stage II colorectal cancer patients and optimising therapy in patients with advanced disease, have focused on molecular and genetic markers. It is hoped that the addition of new therapies to existing drug combinations, as well as further advances in the understanding of colorectal cancer biology, will lead to further improvement in survival and quality of life for patients.     

Advances in preclinical small molecules for the treatment of NSCLC

Background: NSCLC accounts for 85% of all lung cancer cases and is the leading cause of cancer mortality. Advances in the knowledge of molecular events governing oncogenesis have led to a number of novel therapeutic agents targeting specific pathways critical for tumor growth. Objective: To summarize the recent preclinical developments of small molecules for NSCLC therapy. Methods: This review primarily consists of patents and publications between 1997 and 2008. Results/conclusion: Small molecules with known targets, such as inhibitors for EGFR, VEGF, RAS-RAF-MAP kinase pathway, phosphoinositide 3-kinase pathway, histone deacetylase, protein phosphatase, topoisomerase, cyclin dependent kinases, heat-shock protein, tubulin, DNA and MET are reviewed. Other novel small molecules with potent efficacy without target information are also discussed.     

Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment

Introduction: Over the last 15 – 20 years, targeted anticancer strategies have focused on therapies aimed at abrogating a single malignant protein. Agents that are directed towards the inhibition of a single oncoprotein have resulted in a number of useful drugs in the treatment of cancers (i.e., Gleevec, BCR-ABL; Tarceva and Iressa, EGFR). However, such a strategy relies on the notion that a cancer cell is dependent on a single signaling pathway for its survival. The possibility that a cancer cell may mutate or switch its dependence to another signaling pathway can result in the ineffectiveness of such agents. Recent advances in the biology of heat-shock protein 90 (Hsp90) have revealed intimate details into the complexity of the chaperoning process that Hsp90 is engaged in and, at the same time, have offered those involved in drug discovery several unique ways to interfere in this process.

Areas covered: This review provides the current understanding of the chaperone cycle of Hsp90 and presents the multifaceted approaches used by researchers in the discovery of potential Hsp90 drugs. It discusses the phenotypic outcomes in cancer cells on Hsp90 inhibition by these several approaches and also addresses several distinctions observed among direct Hsp90 ATP-pocket competitors providing commentary on the potential biological outcomes as well as the clinical relevance of such features.

Expert opinion: The significantly different phenotypic outcomes observed from Hsp90 inhibition by the many inhibitors developed suggest that the clinical development of Hsp90 inhibitors would be better served by careful consideration of the pharmacokinetic/pharmacodynamic properties of individual candidates rather than a generic approach directed towards the target.     

The preclinical discovery of vosaroxin for the treatment of acute myeloid leukemia

Introduction: Acute myeloid leukemia (AML) represents a disease with a very poor outcome and remains an area of significant unmet need necessitating novel therapeutic strategies. Among novel therapeutic agents, vosaroxin is a first-in-class anticancer quinolone derivative that targets topoisomerase II and induces site-selective double-strand breaks in DNA, leading to tumor cell apoptosis.

Areas covered: Herein, the authors provide a comprehensive review of the preclinical development of vosaroxin. This includes coverage of vosaroxin’s mechanism of action in addition to its pharmacology and of the main studies reported over the past few years with vosaroxin when used to treat adult AML.

Expert opinion: Given that vosaroxin is associated with fewer potential side effects, it may be of benefit to elderly patients with relapsed/refractory AML and to those with additional comorbidities who have previously received an anthracycline and cytarabine combination. Furthermore, vosaroxin also was seen to be active in multidrug-resistant preclinical models. However, further studies have to be performed to better evaluate its place in the armamentarium against AML.     

硼替佐米对卵巢癌SKOV-3/DDP细胞增殖和耐药逆转的影响

目的:探讨硼替佐米对卵巢癌SKOV-3/DDP细胞增殖和耐药逆转的影响和作用机制。方法:采用MTT法检测不同浓度硼替佐米和顺铂(DDP,cisplatin)对SKOV-3/DDP不同作用时间的细胞生长抑制率,以及硼替佐米和DDP合用和单独应用时的细胞生长抑制率;流式细胞术检测细胞凋亡和细胞周期的变化。结果:硼替佐米能够有效抑制SKOV-3/DDP细胞增殖,硼替佐米与DDP合用组的SKOV-3/DDP细胞抑制率较硼替佐米和DDP单用组均明显增强。单独应用硼替佐米细胞周期阻滞于G2/M期,单独应用DDP细胞周期阻滞于S期,两药联合出现更明显的S期阻滞。结论:硼替佐米与DDP具有协同作用,能够逆转SKOV-3/DDP细胞对DDP的耐药性。     

NVP-BEZ235 alone and in combination in mantle cell lymphoma: an effective therapeutic strategy

Objectives: Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma; the complete response rate for standard therapies in use today is 85 – 90%. NVP-BEZ235 inhibits the PI3K/Akt/mTOR signaling axis at the level of both PI3K and mTOR. In this study, we analyzed the inhibitory effects of NVP-BEZ235 on mantle cell lines and its effects in combination with enzastaurin, everolimus and perifosine.

Methods: The effects of NVP-BEZ235 on cell proliferation and apoptosis were evaluated using MTT assay and flow cytometry analysis. The cell cycle analysis was performed applying BrdU incorporation. Western blot analysis was utilized for phosphorylation status evaluation of protein kinases. The interaction between NVP-BEZ235 and enzastaurin, everolimus and perifosine was examined by Chou-Talalay method.

Results: NVP-BEZ235 induced significant increase of apoptosis, both via intrinsic and extrinsic pathways. We found that NVP-BEZ235 inhibited mantle cells growth by induction of G1 arrest. NVP-BEZ235 exerts its antitumor activity even when mantle cells were in contact with bone marrow microenvironment. Enzastaurin, everolimus and perifosine enhanced the cytotoxicity triggered by NVP-BEZ235.

Conclusions: The above results encourage clinical development of NVP-BEZ235 in combination and the possible inclusion of patients with mantle lymphoma in Phase I/II clinical trials.     

The cancer stem cell paradigm: a new understanding of tumor development and treatment

Importance of the field: Cancer is the second leading cause of death in the United States, and therefore remains a central focus of modern medical research. Accumulating evidence supports a ‘cancer stem cell’ (CSC) model – where cancer growth and/or recurrence is driven by a small subset of tumor cells that exhibit properties similar to stem cells. This model may provide a conceptual framework for developing more effective cancer therapies that target cells propelling cancer growth.

Areas covered in this review: We review evidence supporting the CSC model and associated implications for understanding cancer biology and developing novel therapeutic strategies. Current controversies and unanswered questions of the CSC model are also discussed.

What the reader will gain: This review aims to describe how the CSC model is key to developing novel treatments and discusses associated shortcomings and unanswered questions.

Take home message: A fresh look at cancer biology and treatment is needed for many incurable cancers to improve clinical prognosis for patients. The CSC model posits a hierarchy in cancer where only a subset of cells drive malignancy, and if features of this model are correct, has implications for development of novel and hopefully more successful approaches to cancer therapy.     

The discovery and development of romidepsin for the treatment of T-cell lymphoma

Introduction: Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a promising drug for the treatment of T-cell lymphomas. The cellular action of romidepsin results in enhanced histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, influencing cell cycle, apoptosis, and angiogenesis. In phase II studies involving patients with relapsed or refractory of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), romidepsin produced overall response rates (ORR) of 34–35% and 25–38%, with complete response (CR) rates of 6% and 15–18%, respectively.

Areas covered: This review summarizes the development of romidepsin, the mechanisms behind its antineoplastic action and its pharmacology. It also covers its pharmacokinetic and pharmacodynamic properties, as well as the preclinical and clinical data on its activity in T-cell lymphoma.

Expert opinion: Since there are only few effective therapies available for T-cell lymphomas, romidepsin is a valuable option for relapsed/refractory patients with both CTCL and PTCL. It’s also generally well tolerated, and gives potentially durable responses for patients with advanced and symptomatic disease. Combinations of romidepsin with other antineoplastic agents may also further improve drug response and outcomes in T-cell lymphoma.