Current Cancer Drug Targets

We are entering an evolving and exciting era of personalized therapy for acute myeloid leukemia (AML) in 2020 and beyond. Personalized medicine refers to a novel development in the approach to treat a variety of human diseases. Although frequently associated with an eagerly awaited paradigm shift, personalized medicine represents an old concept in the context of new knowledge. Indeed, in the early 20th century, Paul Ehrlich first introduced the advanced concept of designing chemicals to bind and inhibit the growth of specific microbes with little toxicity against host cells and tissues [1]. This approach led to a new era in the treatment and prophylaxis of infectious diseases. Decades later, Charles Brenton Huggins successfully introduced hormonal therapy into the treatment of prostate cancer [2] and further opened the door for targeted treatment strategies in the management of cancer. The advent of the tyrosine kinase inhibitor, imatinib, and the CD20-targeted monoclonal antibody, rituximab, both initially investigated in the late 1990s, eventually revolutionized the care of patients with chronic myeloid leukemia and Non-Hodgkin lymphoma, respectively, and validated the use of targeted therapy in cancer and other human diseases. These exciting new developments have been further augmented by an increased understanding of the interactions between the immune system and cancer cells. As a result, a large number of targeted therapy and immunotherapeutic trials have entered the oncology clinical arena over the past several years. AML is a rapidly progressive myeloid malignancy with the highest mortality rate among all leukemias. Median overall survival is approximately 12 months for all-comers with newly diagnosed AML. However, outcomes are dependent on multiple risk factors at diagnosis, including age, cytogenetics, molecular markers, performance status, and comorbidities. For instance, in younger patients, long-term survival can be achieved in >60% of patients without an allogeneic stem cell transplant in those who have favorable-risk features ascertained by cytogenetics and genomic factors whereas only 10-15% of younger patients with adverse-risk features attain long-term survival and cure [3]. Sophisticated methodologies have already resulted in a progressive shift from a morphology-based classification to one that systematically incorporates genomic data into diagnosis and prognostication [4]. While these advances led to a better understanding of AML biology by highlighting the highly diverse and heterogeneous genomic features of AML, progress in managing AML has been lagging behind that of other cancers for several decades. In fact, highly toxic and potentially fatal therapies implemented in the 1970s remain the standard of care for the vast majority of patients today. Between 1990-2017, only two therapeutic agents were FDA-approved in the United States for the management of AML. Idarubicin, a newer anthracycline formulation, was FDA-approved in 1990 providing perhaps modest benefit but has been used interchangeably with daunorubicin in combination with continuous cytarabine (7+3 regimen) and thus has not transcended clinical care of patients with AML [5, 6]. Gemtuzumab ozogamicin, an antibody drug conjugate targeting CD33 with a DNAdamaging linker was initially approved by the FDA in 2000 under the accelerated approval mechanism for relapsed/refractory AML based on encouraging findings from a single-arm phase 2 study [7]. However, a confirmatory randomized phase 3 study in newly diagnosed AML patients revealed toxicity concerns and did not corroborate an improvement in clinical outcomes [8]. Thus, GO was withdrawn from the market in 2010. The AML community has since been desperately and urgently waiting for novel therapeutic agents that would provide clinical activity to help a challenging patient population of high unmet need. Since 2017, there have been 8 new drugs approved by the FDA for AML launching a new era of targeted treatment approaches that hold promise for improving outcomes in this patient population. However, despite the expanded armamentarium for AML, only a proportion of patients are expected to benefit from these personalized treatment options and resistance is an unfortunately common theme. The great progress in understanding the pathophysiology of AML as well as the related discovery of new drug targets, in concert with recent advances in immunotherapy, has sparked a wave of innovative combinatorial treatment strategies that are expected to move the field forward with treatments that can provide durable remissions. This issue of Current Cancer Drug Targets aims to provide a comprehensive overview of the shifting landscape in AML diagnosis and management, with a focus on recent progress and persisting challenges. Two review articles elaborate on the role of immunotherapy in AML. The manuscript by Thummalapalli, Knaus, Gojo and Zeidner provides an overview of the current state of knowledge regarding the use of immune checkpoint inhibition as well as a clinical update of ongoing trials in this field. The contribution by Agrawal and colleagues summarizes the recent progress and persisting obstacles in cellular immunotherapies. Three manuscripts propose a comprehensive overview of genomics and targeted therapies in AML. The article by Horibata, Alyateem, DeStefano and Gottesman discusses the impact of genomics in the decision-making process and highlight recent advances in the development of targeted AML therapies. The authors further expand on persisting challenges in AML management, including off-target toxicity and the development of drug resistance. Hogan, Williams and Knapper focus on the biology of FLT3 mutated AML, the exciting clinical development of FLT3-targeted agents and the future outlook for these compounds in the leukemia treatment landscape. The contribution by Fathi and Becker update the reader on the role of IDH inhibitors in AML, thereby discussing their mechanism of action with an emphasis on differentiation induction as a central mechanism of anti-leukemic activity but also of clinical toxicity. The authors further provide future directions with respect to integrated IDH targeting within existing anti-AML treatment regimens. Finally, Horton, Wileman and Rushworth report on the potential therapeutic exploitation of cellular processes such as autophagy and extracellular vesicles in AML and related diseases. In sum, in this special issue of Current Cancer Drug Targets, a multi-disciplinary and international team of leukemia clinicians and basic scientists discusses multiple topics relevant to AML biology, diagnosis, treatment and drug development. This is an exciting time for the AML community and the editors and authors hope that this issue will provide a source of information and contribute to stimulate interest in this rapidly evolving field.

As the Guest Editors of this special issue of the Journal “Current Cancer Drug Targets”, we are pleased to present you the current issue focused on “Current Cancer Drug Development Strategies” Cancer and non-controllable inflammation (also termed nonresolving inflammation) constitute enormous public health burdens worldwide and the treatment of these highly complex diseases remains a technological bottleneck. There is an urgent need to develop new and innovative technologies that could improve the current treatments, and identify new cancer drug targets for intervention. Because cancer and the nonresolving inflammation diseases are complicated, our treatment strategies should be accordingly multiplex. This thematic issue of Current Cancer Drug Targets covers medicinal nanotechnology, photodynamic therapy (PDT), PI3K/Akt pathway inhibition, drug combination for comprehensively controlling key cancer metastatic pathways, animal models for screening cancer drug target. The advent of nanomedicine holds great promise to improve the treatment of various diseases, including cancer. In the context of nanomedicine-based therapeutics, the unique properties of nanoparticles make it easier for targeted drug delivery to cancer tissues with multi-functionality. Xie et al., discussed the characteristics of cancer including tumor angiogenesis, abnormalities in tumor blood vessels, uncontrolled cell proliferation markers, multidrug resistance, tumor metastasis, cancer cell metabolism, and tumor immune system that provide opportunities and challenges for nanomedicine to be directed to specific cancer cells and portrayed the progress that has been accomplished in the application of nanotechnology for cancer treatment. As cancer therapy requires close collaboration among clinicians, biological and material scientists, and biomedical engineers with the joint efforts of researchers in various fields, the information presented in this review can provide useful references for further studies on developing effective nanomedicine for treatment of cancer. As a representative of the drug delivery system, mesoporous silica nanoparticles (MSNs) have shown great potential as good candidates for drug delivery and biomedical application. Pu et al., described the most recent progress in silica-assisted drug delivery and biomedical applications using different types of Cargo, including (1) anticancer drugs, (2) antibacterial agents, (3) gene delivery, (4) photodynamic therapeutic agents, (5) bioimaging agents and others. The collected information about the in vitro and in vivo bioactivity of MSNs and the current status of preclinical trials about drug-loaded MSNs in this review could provide useful references for the rational design of MSN-based drug delivery systems for clinical use. Relative to inorganic materials, organic materials such as block copolymers have shown wider applications in drug delivery. Poly(lactic-co-glycolic acid) (PLGA) was used to entrap curcumin (CUR) for treating ulcerative colitis (UC), a chronic relapsing disease by Ma et al. They compared the oral efficacy of CUR-loaded microparticles (CUR-MPs) and CUR-loaded nanoparticles (CUR-NPs) in treating UC, and found that CUR-NPs showed a superior therapeutic efficacy in alleviating colitis in comparison to CUR-MPs. The research provided the evidence that the particle-based UC therapy exhibited size-dependent behavior. Cao et al., used paclitaxel-loaded poly(L-phenylalanine)-b-poly(L-aspartic acid) nanoparticles to enhance penetration of paclitaxel to multidrug resistant cells. The pharmacokinetics and the biodistribution results demonstrated that drug loaded in nanoparticles could effectively reduce plasma peak concentration and extend plasma circulating time as compared to paclitaxel injection, and the nanoparticles could markedly, passively target the mononuclear phagocyte system (MPS)-related organs. Their study provided an effective approach for the development of anti-tumor nanomedicine with drug-resistant reversal effect. Recently, plant-derived medicinal compounds are becoming an important research area for cancer drug development, especially as safe and effective agents for cancer metastasis chemoprevention. Zou et al., reviewed the great potential of a naturally abundant pentacyclic triterpenoid compound ursolic acid (UA) used as a candidate drug in the field of cancer therapy relating to the suppression of tumor initiation, progression and metastasis. In this review, they introduced the molecular anticancer mechanism of UA, and highlighted its important role in chemoprevention of tumor metastasis. They also summarized the current development of novel UA derivatives, pro-drugs, co-drugs as well as nanoformulations, such as liposomes, chitosan, polymers and mesoporous silica nanoparticles used as a candidate drug for potential application in the field of cancer therapy and cancer metastasis chemoprevention. The information presented in this review can provide useful references for further studies in making UA a promising anti-cancer drug, especially as a prophylactic metastatic agent for clinical applications. Targeted drug/gene delivery systems are widely used in cancer treatment since they can improve tumor targeting, reduce the side effect of chemotherapy agent as well as enhance the efficacy of gene transfection into target cancer cells. Yan and coauthors investigated the enhanced anticancer efficacy of one novel nano complex named as “AuNC/PEI/miRNA/HA”, which could both effectively enhance gene delivery efficiency and regulate gene expression in the context of miRNA interference. Combining gene and PDT, the novel nano complex could significantly promote apoptosis and improve TIMP-3 mRNA expression in Bel-7402 cell. They are developing this nanocomplex as an efficient and safe carrier for microRNAs to hepatocellular carcinoma (HCC) treatment. Jiang et al., introduced a novel nano drug delivery system based on the third-generation polyamidoamine dendrimer as a nanocarrier for PDT. The optimized system significantly improved the solubility of ZnPcC4 with a higher singlet oxygen production efficiency. Their results provided a facile approach for the design and fabrication of composite nanomaterials with remarkably boosted anticancer effect. Combination therapy is an effective strategy for comprehensive cancer therapy. Xu et al., investigated a novel quadruple drug combination consisted of mifepristone, aspirin, lysine and doxycycline (HAMPT) for synergistically controlling key cancer metastatic pathways. By using this combination therapy, a good adhesion inhibited ratio was exhibited, and cancer cell migration was inhibited. Moreover, the in vivo experiment indicated that HAMPT could suppress the metastasis of CT-26 cells to mouse lungs in a dose-dependent manner without marked side effects. Their study demonstrated that HAMPT is a safe, effective and affordable cancer metastatic chemopreventive agent that can effectively prevent cancer recurrence and metastasis. Phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to play important roles in cancer cell growth, invasion, migration and metastasis. Liu et al., explored the anti-metastatic activities of pan-PI3K inhibitor ZSTK474 in prostate cancer DU145 cells. Their work showed that ZSTK474 potently inhibited DU145 cell migration, invasion and adhesion by negatively regulating the expression of VEGF, Integrinβ1, MMPs and HIF-1α proteins, which are well-known to be related to angiogenesis and metastasis. The in vitro and in vivo results demonstrated the potential anti-metastatic effect of ZSTK474 as a novel PI3K inhibitor in prostate cancer. Finally, Wang et al., systematically overviewed the pros and cons of animal models to provide information to researchers in pharmaceutical chemistry and bio-chemistry field for smartly selecting the suitable predictive model for anti-cancer drugs with the different mechanisms. They also emphasized the pharmaceutical challenges behind and ahead. The information will help us select the optimal in vitro or in vivo experimental model and to correctly respond to the presence or potential side effects of drugs for the patients providing a reference to clinical trials.

Current development of targeted therapy and multidisciplinary approach for new treatment modalities, has contributed to increase the outcome in cancer patients. Based on the new knowledge of molecular features of the tumor, it is urgently needed to clarify some aspects on new treatments. Actually the innovative approach in oncology is represented by: a) the development of anticancer targeted drugs; b) growing member of elderly cancer patients; c) constant augmentation of so-called “cancer survivors”; d) infection-related neoplasms (HIV, HPV, EBV, HHV8 and Hepatitis Virus); and lastly, e) the colossal healthcare cost to support all these new treatments. In order to comprehend well these “new” issues for the upcoming future, it is necessary to make some reflections [1]. The end of the 2nd Millennium has been characterized by the introduction of new molecules in cancer treatment allowing “target therapy”. Targeted drugs are principally small inhibitor molecules (i.e. erlotinib, imatinib etc.) and monoclonal antibody (i.e. trastuzumab, rituximab, ipilimumab, nivolumab, etc.) that interfere directly in the molecular mechanism of proliferating pathways, reducing traditional toxicities of antiblastic chemotherapy (AC). The mechanism of action of these new targeted molecules is universal in all neoplastic cells carrying the corresponding cancer target, but some of these have been approved by drug labeling studies. Efficacy failure is recorded when the therapeutic indication has been extended to other types of cancer (e.g., erlotinib in metastatic pancreatic cancer). However, an appropriate study on resistance, efficacy of long-term treatment and outcome is mandatory for tailored cancer therapies. Furthermore, new drugs indication must only be approved by an appropriat clinical trial. Currently these issues exist for drugs with strong evidence to improve personalized label or schedule (i.e., cetuximab used only in KRAS mutational status, duration of adjuvant trastuzumab); or an existing anticancer agent for another therapeutic indication (i.e., imatinib in sclerodermatous). Often, pharmaceutical corporations do not support these studies due to rarity of the disease. These problems occur recurrently in the context of a low subset of targeted population (i.e., cancer with mutations frequency lower than 2%) [2]. Targeted therapy has introduced new economic reflections: for example substituting traditional chemotherapy (often needs vascular access and intravenous infusions) to oral small molecule inhibitors, eliminates some costs by moving therapy from the hospital to home [3]. On the other hand, if therapy includes monoclonal antibodies (mAbs), the costs dramatically increase (Table 1) calculated that the cost of $30,790 of the eight weeks treatment regimens containing bevacizumab or cetuximab in colorectal cancer was calculated, compared with $63 for the same period of 5-fluorouracil, leucovorin and oxaliplatin regimen [4]. Current treatments of cancer are derived through validated clinical trials, that include, often, innovative patented drugs. Nevertheless, global contemporary model of community healthcare systems highlights that new therapeutic care must be carried out at an equal or lower cost. Besides, trials evaluating the precise economic impact of cancer treatments are still few. Advanced methods to assess cost-effectiveness, cost-utility and cost-benefit in the cancer organizations have been introduced. Such as the National Institute for Health and Clinical Excellence (NICE). NICE has established several clinical Advisory committees, which stimulate Academic and Pharma societies to design studies, including economic models for personalized healthcare [5]. Personalized medicine is a promising model which includes genomic tests due to specific tailored treatments [6]. It is well known that Pharmacogenomics tests, performed before drug treatment, minimize toxicity and maximize benefits and provide higher quality of life [7]. NICE also provides a method to measure Quality-Adjusted Life-Years (QALY), combining data on outcomes, analytical assay and cost-effectiveness for entire treatment. The up-coming methods to measure the QALYs will lead to multidisciplinary treatment approach for decreasing the costs of these treatments. Progress in cancer treatment is driven by cumulative knowledge of the molecular cancer pathways, and the subsequent development of systemic agents that inhibit critical neoplastic pathways. However, not all new molecules with biological target are automatically approved. The base for their US Food and Drug Administration (FDA) approvals differ: an upgrading in overall survival (OS) compared with a current therapy is not always required; [8] toxicity profiles and progression-free survival are also considered as important factors [9]. Finally, we contemplate that the recent progresses have provided exceptional opportunities to identify prognostic and predictive markers of efficacy of antiblastic treatments [10]. Genetic markers can be used to identify patients who will benefit from therapy, excluding patients at high risk to develop severe adverse events, and adjust dosing [11]. Furthermore, trials evaluating the pharmacoeconomic impact of genotyping assay on cancer therapy are still few. Also, the major issue to consider for genotyping is the need to interpret laboratory data results by an oncologist [12]. However, inadequate education of the physicians regarding Pharmacogenomics field has been observed [13]. The contemporary knowledge of healthcare professionals concerning pharmacogenomics is still limited, and teaching programs are poor in this field. However, new method to measure cost-effectiveness in cancer therapy have already been proposed [14].

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