Overview of Current Targeted Anti-Cancer Drugs for Therapy in Onco-Hematology

The upgraded knowledge of tumor biology and microenviroment provides information on differences in neoplastic and normal cells. Thus, the need to target these differences led to the development of novel molecules (targeted therapy) active against the neoplastic cells’ inner workings. There are several types of targeted agents, including Small Molecules Inhibitors (SMIs), monoclonal antibodies (mAbs), interfering RNA (iRNA) molecules and microRNA. In the clinical practice, these new medicines generate a multilayered step in pharmacokinetics (PK), which encompasses a broad individual PK variability, and unpredictable outcomes according to the pharmacogenetics (PG) profile of the patient (e.g., cytochrome P450 enzyme), and to patient characteristics such as adherence to treatment and environmental factors. This review focuses on the use of targeted agents in-human phase I/II/III clinical trials in cancer-hematology. Thus, it outlines the up-to-date anticancer drugs suitable for targeted therapies and the most recent finding in pharmacogenomics related to drug response. Besides, a summary assessment of the genotyping costs has been discussed. Targeted therapy seems to be an effective and less toxic therapeutic approach in onco-hematology. The identification of individual PG profile should be a new resource for oncologists to make treatment decisions for the patients to minimize the toxicity and or inefficacy of therapy. This could allow the clinicians to evaluate benefits and restrictions, regarding costs and applicability, of the most suitable pharmacological approach for performing a tailor-made therapy.


Introduction
Targeted therapies are developed to encompass the nonspecific toxicity associated to standard chemo-drugs and also to ameliorate the efficacy of treatment. Biological agents can be used alone, but very often a combination of targeted molecules and conventional anti-tumor drugs is used. This new strategy aims to a selectively killing of malignancy cells by targeting either the expression of specific molecules on cancer cell surface or the different activated molecular pathways that directed to tumor transformation [1]. New therapeutic approaches include a combination of "old" anticancer drugs (i.e., chemotherapies) and innovative molecules (targeted agents). These procedures are planned to mark both primary and metastatic cancer cells. The current classification of cancer-hematology targeted drugs includes monoclonal antibodies (mAbs), small-molecule inhibitors (SMIs), interfering RNA (iRNA), microRNA, and oncolytic viruses (OV). Their mechanisms of action can be either tumor specific (by interfering with cancer cell membrane biomarkers, cell-signaling pathways, and DNA or epigenetic targets), or systemic, through triggering of the immune responses [2][3][4].
Currently, scientific evidence is still low, to address therapeutic drug monitoring of mAbs and SMIs. In this scenario, their combination with adjuvant therapies may represent a promising cancer treatment approach [5].
In 2001, the first selective ABL Tyrosin Kinase inhibitor (TKI, Imatinib) was approved by the US Food and Drug Administration (FDA) [6]. This was quickly followed by the monoclonal antibody marking the CD20 antigen (anti-CD20mAb, Rituximab) [7]. Both agents accounted the revolution in the management of patients with Chronic Myeloid Leukemia (CML) and non-Hodgkin's lymphoma (NHL), respectively. These drugs guarantee around 80% response rate; on the other hand, drug-resistance is still a limitation, and new generation TKIs are being developed to by-pass these matters.
Currently, various new molecules are developed against specific tumor cell targets. Among these, histone deacetylase inhibitors (HDACi) and DNA hypomethylating agents target genetic/epigenetic determinants central for tumor growth ablation. New peptide vaccines targeting novel tumor-associated antigens, alternative checkpoint inhibitors, and chimeric antigen against T receptor (CAR-T) of the lymphocytes are being developed for the patients who have failed classical immunotherapy (often anti-PD1/anti-PD-L1). Newer SMIs targeting a variety of oncogenic signaling are being advanced to overcome the emerging of resistance phenomena to the existing targeted drug procedures [8]. Above Table 1 reviews currently open phase I/II/III clinical trials for onco-hematologic patients. The data in the table were collected from clinicaltrils.gov (accessed on June 2019). It may provide a useful implement to oncologist who treat relapsed refractory hematology malignancy.
Thanks to unique mechanisms of action these drugs are part of the therapy for many anticancer protocols, including lung, breast, pancreatic, and colorectal tumors, as well as lymphomas, leukemia, and multiple myelomas (MM). Also, targeted therapies call for new approaches to evaluating treatment effectiveness, and to assess the patients' adherence to treatment [9].
Although targeted drugs, primarily the mAbs administration, are better tolerated than conventional chemotherapy, they are recorded numerous adverse events, such as cardiac dysfunction, hypertension, acneiform rash, thrombosis, and proteinuria [10]. Since, SMIs are metabolized preferentially by cytochrome P450 enzymes (CYP450), the pharmacokinetics variation and multiple drug interactions should be present [11].
Finally, targeted therapy has raised new questions about the tailoring of cancer treatments to each patient's tumor profile, the estimation of drug response, and the public reimbursement of cancer care. In agreement with these and other criticisms, the intention of this review is to provide information about the overall biology and mechanism of action of target drugs for onco-hematology, including overall pharmacodynamics due toxicities, and eventually inefficacy of the therapy [12]. The well-noted correlation between the individual genomics profile and overall pharmacokinetic are reported below. In addition, the economic impact of these drugs, which can exceed several-fold the cost of traditional approaches, may become a major issue in pharmacoeconomics; an early evaluation of outcomes and challenges are also reported in this issue.

The Biological Mechanism of Action of the Targeting Agents
Traditional cytotoxic chemotherapy works mainly through the inhibition of cell division like as cytoskeleton inhibitors (i.e., tecans, vincristine)analogues of nucletides (i.e., 5-Fluorouracil, Gemcitabine). So, each normal cell in mitotic stage (e.g., hair, gastrointestinal epithelium, bone marrow) is affected by these drugs. In contrast, the mechanism of action of targeted agents block specifically the proliferation of neoplastic cells by interfering with specific pathways essential for tumor progression and growth ( Figure 1). It is true that some of these molecular targets could be present also in normal tissues, but they are often abnormally expressed in cancer tissues because of genic alterations. present also in normal tissues, but they are often abnormally expressed in cancer tissues because of genic alterations. Figure 1. Schematic of pathway inhibition by targeted agents and their effects on cell proliferation, apoptosis, metastasis and angiogenesis. Receptors for growth factors (VEGFR, FGFR, PDGFR) activate intracellular receptor tyrosine kinases (RTKs) and the downstream RAS/RAF/mitogenactivated protein extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, and promote the growth, migration, and morphogenesis of vascular endothelial cells, thus increasing vascular permeability.

Monoclonal Antibodies
In the last decade, about 30 mAbs have been approved, almost the 50% of them for the hematology-cancer therapy. The backbone of a mAb includes the fragment antigen binding (Fab), which recognizes and engage antigens, thus targeting the specific counterpart on cancer cells which is the objective of such therapies [13]. These antibodies agent, either as native molecules or conjugated to radioisotopes or toxins (viral molecules to interfere with cell vitality) exert their antineoplastic effects through different mechanisms: by engaging and arming host immune effectors (i.e., natural killer cells and the complement) against target cells; by binding to receptors or ligands, thereby interfering with essential cancer cell proliferation pathways; or by carrying a "lethal cargo", such as a radioisotope or toxin, to the target cell [14,15]. Because they are protein in structure, mAbs denatured in the gastrointestinal tract, and for this reason, they are administered intravenously. In this way, they do not undergo hepatic metabolism thus escaping significant drug interactions via CYP450 pathway.
Latest 30 years, as biotechnology has evolved, the design of mAbs has changed. Immunized mice developed early molecules in this class against target antigens. The resulting mAbs comprised the entire murine immunoglobulins (Igs), which were, hypothetically, carrying a risk of antigenic reaction during parenteral administration. The primary adverse events for patients treated with these new drugs is forming anti-mouse immunoglobulin antibodies, which could counteract the effect of the therapeutic mAbs. To decrease these adverse reactions, was developed mAbs contain an enlarged proportion of human Ig components to reducing murine Ig components. So mAbs are defines as: chimeric antibodies (about 65% human), humanized antibodies (95% human), and human antibodies (100% human) [16].
General precautions of mAbs include: (a) Co-administrations of vaccines may be avoided; (b) Herpes and Pneumocystis prophylaxis recommended in therapy influencing the immune surveillance system (i.e., Anti-CD52); Figure 1. Schematic of pathway inhibition by targeted agents and their effects on cell proliferation, apoptosis, metastasis and angiogenesis. Receptors for growth factors (VEGFR, FGFR, PDGFR) activate intracellular receptor tyrosine kinases (RTKs) and the downstream RAS/RAF/mitogen-activated protein extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, and promote the growth, migration, and morphogenesis of vascular endothelial cells, thus increasing vascular permeability.

Monoclonal Antibodies
In the last decade, about 30 mAbs have been approved, almost the 50% of them for the hematology-cancer therapy. The backbone of a mAb includes the fragment antigen binding (Fab), which recognizes and engage antigens, thus targeting the specific counterpart on cancer cells which is the objective of such therapies [13]. These antibodies agent, either as native molecules or conjugated to radioisotopes or toxins (viral molecules to interfere with cell vitality) exert their antineoplastic effects through different mechanisms: by engaging and arming host immune effectors (i.e., natural killer cells and the complement) against target cells; by binding to receptors or ligands, thereby interfering with essential cancer cell proliferation pathways; or by carrying a "lethal cargo", such as a radioisotope or toxin, to the target cell [14,15]. Because they are protein in structure, mAbs denatured in the gastrointestinal tract, and for this reason, they are administered intravenously. In this way, they do not undergo hepatic metabolism thus escaping significant drug interactions via CYP450 pathway.
Latest 30 years, as biotechnology has evolved, the design of mAbs has changed. Immunized mice developed early molecules in this class against target antigens. The resulting mAbs comprised the entire murine immunoglobulins (Igs), which were, hypothetically, carrying a risk of antigenic reaction during parenteral administration. The primary adverse events for patients treated with these new drugs is forming anti-mouse immunoglobulin antibodies, which could counteract the effect of the therapeutic mAbs. To decrease these adverse reactions, was developed mAbs contain an enlarged proportion of human Ig components to reducing murine Ig components. So mAbs are defines as: chimeric antibodies (about 65% human), humanized antibodies (95% human), and human antibodies (100% human) [16].
General precautions of mAbs include: (a) Co-administrations of vaccines may be avoided; (b) Herpes and Pneumocystis prophylaxis recommended in therapy influencing the immune surveillance system (i.e., Anti-CD52); The mAbs were designed to affect several cellular pathways. An angiogenic inhibitor (i.e., Anti-VEGF) was currently investigated in NHL, MM, and myeloproliferative disorders [17]. The major side effect regardless the risk of ischemic events.
Immunomodulators aimed to achieve blocking of inhibitory molecules on the cell surface of immune effectors (i.e., Anti PD-1, anti-CD30, anti CD52, anti-CTLA-4, and anti-CD80), were approved for the treatment of patients with Hodgkin Lymphoma (HL).
The first targeted therapies have developed through the study of the over/expression of markers on the surface of tumor cells (on lymphoma and leukemia cells) including the cluster of differentiation 20, 33, and 52 (CD20, CD33, and CD52). Targeting this molecule affects the overall humoral immune response, as CD20 is also expressed on normal lymphocyte B. This estimation has led to the administration the anti-CD20 mAb Rituximab for the treatment of autoimmune diseases such as rheumatoid arthritis [18], and NHL [19].
Moreover, mAbs might induce tumor cell death through direct and indirect mechanisms, all prominent in blocking several and different oncogenic pathways. mAbs are effective at multiple levels: surface molecules (neutralizing ligand-specific receptor interaction), receptors (competitive with a ligand for binding); receptor signaling (signal blocking), or intracellular molecules. Therapeutic mAbs, which are typically water soluble and large molecular weight (about 160 kDa), target extracellular molecule-inducing signals, such as receptor-binding sites and ligands.
Noteworthy, Brentuximab vedotin have a new peculiar mechanism of action. It is an anti-CD30 antibody-drug conjugate (mAbC) that delivers an anti-tubulin toxin that induces apoptotic cell death in CD30-expressing tumor cells. Brentuximab vedotin is a mAb with a regular action involving a multi-step progression: binding to CD30 on the cell surface recruits internalization of the mAbC-CD30 complex, which then transfers to the cytoskeleton structures, where the released toxin, the monoauristatin-E, rescinds the microtubule complex, inducing cell cycle arrest and apoptotic death of the CD30-expressing cell in replication stage. However, classical Hodgkin's lymphoma (HL) and T-anaplastic large cell lymphoma (ALCL) express CD30 as an antigen on the surface of their malignant cells [20].

Small Molecule Inhibitors
SMIs are chemical agents with low molecular weight (inferior to 1 kDa) capable of entering into the targeted cells, thus blocking signaling pathway and interfering with downstream intracellular protein systems (i.e., TK signaling). These molecules consist of TKI, BKI, Aurora Kinase Inhibitors (AKI), proteosome Inhibitors and HDAC inhibitors. Tyrosine Kinases phosphorylate specific amino acid residues of intracellular substrates affecting angiogenesis and cell growth in normal and malignant tissues.
The SMls differ from mAbs in many ways: (i) they are usually orally administered rather than parenterally infused; (ii) they are generated via a step-by-step chemical practice, a method that is often much less expensive than the bioengineering (i.e., recombinant DNA techniques) required for mAbs generation [18]; (iii) they reach fewer definite targeting than mAbs, as marked in the multitargeting nature of the kinase inhibitors [21].
In contrast to mAbs, most of the SMIs are metabolized by the CYP450 enzymes family, which may consequence in drug-drug interactions with molecules such as warfarin, azole antimicotics, viral anti-protease, and the St. John's wort, known as unyielding CYP450-inhibitors [22].
The mAbs have administered once every one-to-four weeks due to pharmacokinetic of T 1/2 ranging from few days to few weeks. While most SMIs have half-lives of few hours and necessitate daily dosing., with the exception of few molecules (i.e., bortezomib) which is given intravenously, SMIs are administered per os (orally).
Imatinib is the first FDA-approved SMIs (since 2002) for the treatment of CML. It inhibits a constitutive TK activities resulting from the translocation of chromosomes 9 and 22 (the Philadelphia chromosome), involving BCR and Abl genes. Because this molecular anomaly occurs in essentially all patients with CML, imatinib therapy results in a complete hematologic response in 98% of them [23]. Novel TKI molecules to overcome the imatinib resistance due to ABL T315I was developed, Bosutinib [24], Dasatinib [25], Nilotinib [26], and Ponatinib [27]. Furthermore, these small molecules are not able to prevent cerebral metastasis [28].
JAK family (JAK1, JAK2, and JAK3) members mediate cytokine signaling via downstream activation of the STAT family of transcriptional regulators. Activated STATs endorse multiple cellular actions, like differentiation, proliferation, migration, and apoptosis. In particular, JAK2 is mediated hematopoiesis via GM-CSF, leptin, IL3, erythropoietin, and thrombopoietin [29]. Activation of JAKs are induced conformational changes of ligand-binding to cytokine receptors, which engage phosphotyrosine-binding domains and/or SRC homology-2, which leads to activation of STAT, Ras-MAPK, and PI3K-AKT signaling pathways. Mutations in JAK2 exon 12 in pseudokinase domain (JH2) and JAK2 Val617Phe in exon 14 have been identified in approximately 4% and 90% of PV cases respectively. Several agents to interfere with JAK/STAT pathway were deigned: Itacitinib is a selective JAK1 inhibitor [30]; Momelotinib and Ruxolitinib are both JAK1-2 inhibitor [31,32].
MET, is a receptor tyrosine kinase that, after binding with hepatocyte growth factor (HGF), activates the PI3K and MAPK pathways. Over-expression of MET gene and exon-14-skipping mutations are characteristic abnormalities causing increased MET signaling progression. Cabozantinib is unique MET Inhibitor studied in phase 1b study in patients with relapsed MM [33].
BRAF is a downstream signaling mediator of KRAS, which activates the MAP kinase pathway. BRAF mutations are found in about 99% of cases of hairy cell leukemia [55] and in several cases of MM. To date, Dabrafenib and Vemurafenib are FDA-approved for BRAF V600E-positive malignant melanomas, but clinical trials of phase 1-2 were currently performed [55].

Bruton's Tyrosin Kinase Inhibitor
BTK is a cytoplasmic TK essential for B-lymphocyte development, differentiation, and signaling. As known, humans X-linked agammaglobulinemia (XLA) caused by mutations in the BTK gene (usually D43R and E41K). Activation of BTK triggers step by step signaling events that culminates in the cytoskeletal rearrangements by Ca 2+ recruitments and transcriptional regulation involving nuclear factor-κB (NF-κB). In B lymphocytes, NF-κB bind the BTK 5 UTR gene promoter and active gene transcription, whereas the B-cell receptor-dependent NF-κB signaling pathway requires functional BTK [56,57].

Histone Deacetylase (HDAC) Inhibitors
Gene expression is regulated primarily by histone acetylation and deacetylation mechanism; this process is essential for relaxing the condensed chromatin and exposes the promoter regions of genes to transcription factors. On the contrary, deacetylation catalyzed by histone deacetylases (HDACs) results in gene silencing [59]. In leukemic cells, this equilibrium is disturbed, and therefore, HDAC inhibitors emerged as a striking therapeutic approach to revise therapy. Unlike, clinical activity of monotherapy with an HDAC inhibitor was low, with ORR of 17% for vorinostat and 13% for mocetinostat [60], and no clinical response was achieved with entinostat monotherapy [61]. In addition, Belinostat has been tested in elderly patients with relapsed AML [62]. Since it is primarily metabolized by UGT1A1; the initial dose should be reduced if the beneficiary is acknowledged to be homozygous for the UGT1A1*28 allele [63]. Therefore, current studies focus on combination regimens of HDAC inhibitors with other epigenetic agents are still ongoing.

Proteosome Inhibitors
The proteasome is the latest promising molecular target for cancer therapy, a large multimeric [64]. The proteasome is a protein complex that degrades the damaged proteins, and neoplastic cells are highly needy on increased protein production and degradation. It has a crucial role in cell signaling, cell survival, and cell-cycle progression. For these issues, proteasome inhibition is a core of therapy in lymphoid malignancies. Furthermore, proteasome inhibitors, such as bortezomib [65] and carfilzomib [66], are currently integrated into major regimens for multiple myeloma (MM) and mantle cell lymphoma (MCL) patients. Recently, proteasome inhibitors have also been used for the treatment of the relapsed/refractory setting for other NHLs, such as follicular cell lymphoma (FCL) [67,68].     Change in the frequency of breathing, lack of or irregular menstruation, lower back, side, or stomach pain, mood or mental changes muscle pain or twitching, nausea or vomiting nervousness or restlessness swelling of the feet or lower legs unpleasant taste unusual tiredness or weakness, chills, fever, joint pain, sore throat, unusual bleeding or bruising.

Pharmacogenetics, Overall Pharmacokinetics
Genetic tests for targeted cancer therapy detect either acquired mutations in the DNA of cancer cells and or polymorphisms in all germinal cells. Genotyping the cancer cells can help guide the type of targeted treatment, and it can predict who may respond to planned therapy and who is not likely to have benefited.
Researchers have extensively studied these variants in genes in order to better understand cancer and to develop drugs to interfere with a specific step in cancer growth while doing minimal damage to normal cells. The first example was Dasatinib and Nilotinib designed to by-pass the acquired mutation T315I in Abl gene in LMC patients. Unluckily, not every cancer has these acquired mutations, and various hematologic-cancers cells without this genetic signature cannot benefit to personalized treatments.
Pharmacogenomic tests are important, also, for the pharmacoeconomic issue: targeted drugs are expensive, and they generally work efficacy only in cancer patients who carried a genetic marker. Genetic testing prior to beginning therapy is necessary to match the treatment up with the patients and cancers likely to benefit from them. In contrast, chemotherapic drugs are cheaper, but it based on the paradigm of the "trial and error" leading the hospitalization during treatments. Recently, to reduce pharmaceutical expenditure, a combination of 2 SMIs blocking 2 mutated genes (BRAF and MET) are performed in the unique formulation (encorafenib + binimatenib) for melanoma therapy. So, the route is also drawn for the onco-hematology [137].
The most common targeted cancer drugs for which tests are available include: Drugs that block growth signaling binding to receptors on the cell surface Small molecules inhibitors are able to cross the cell membrane and block downstream the growing signals in the specific active site.
These pharmacogenetic tests are used to help adjust drug dosage for certain cancers. They help to inform the oncologist as to whether certain targeted cancer drugs may or may not work.

Outcomes and Challenges
Generally, chemotherapy is administered intravenously in an ensured infusion area. Therefore, patient adherence to treatment regimens is gladly reviewed. Delays and omissions in chemotherapy dosages, whether they are the result of patient preference or treatment-related either toxicities or resistance, are immediately recognized and documented. In contrast, most SMIs (almost all are oral formulation) administered at home on a long-term daily scheduling, could be difficult to recognize adverse events in real time. Thus, the task of assessing patient adherence more closely resembles that encountered with therapies for chronic diseases such as diabetes and hypercholesterolemia, and in so-called "frail patients". Finally, a few studies published to date shown high variability and unpredictability about patient adherence to oral cancer treatment regimens [138].
Targeted therapy offers new means to determine the best possible treatment. Moreover, estimation of treatment success could not be based on the reduction in neoplastic volume and/or evaluation of toxicity through the degree of myelosuppression severity as well as traditional chemotherapy. Targeted therapies could convey a clinical benefit by stabilizing tumors, rather than reducing the progression of the neoplastic population cells. It also must necessitate to a paradigm shift in the evaluating the effectiveness of therapy. To set up the optimum of targeted drugs in terms of dosing and efficacy, must be evaluated progressively several endpoints, such as tumor metabolic activity on positron emission tomography (PET) scans, levels of circulating neoplastic cells, and following levels of target molecules in tumor tissue [139]. These actions introduce complexity and cost to medical activity. Also, repeated biopsies of tumor tissue may be untimely for patients and improper to institutional evaluation boards.
Even though these procedures introduces new economic considerations: (i) oral SMIs eliminate treatment costs associated with the hospitalized intravenous infusions; (ii) the biotechnical production of mAbs can improves costs exponentially; (iii) need to genotype or phenotype tumor tissue; and (iv) new competencies for oncologist about pharmacogenomic testing [140].
In term of the expenses, the targeted therapy is widely most expensive than traditional approaches. For example, in colon cancer, multidrug treatment regimens containing bevacizumab or cetuximab increase the cost to about 500-fold ($30,790 for 8 weeks of treatment), compared with fluorouracil/leucovorin-based regimen ($63 for the same period) [141].
Based on this consideration, clinicians and laboratorists have a duty to cooperate in evaluating the advantages and limitations, particularly regarding costs and applicability, of the pharmacogenomic tests most appropriate for routine incorporation in clinical practice [142].

Conclusions and Future Outlook
For decades, the hallmark of anticancer treatments has based on the cytotoxic chemotherapy. These molecules rapidly target mitotic cells, including, unluckily, not only cancer cells but also, normal tissues in physiological growing phase. As a result, many patients develop the general adverse drug reaction (ADR) toxicities such as gastrointestinal symptoms, myelosuppression, and alopecia.
The medical approach based on chemotherapy alone, or in combination with surgical, and/or radiation, has reached doubtful therapeutic advances in spite of many significant enhancements in such treatments. While chemotherapy rests the primarily support of the current treatment in onco-hematology, it is limited by a narrow therapeutic index, noteworthy toxicity leading to treatment discontinuations and frequently acquired resistance.
The targeted molecules are drugs manufactured to interfere with specific proteins necessary for tumor growth and progression.
The new oncologic challenges of the 3rd millennium are based on the developments of the targeted therapy, including OV, interfering RNA molecules, and microRNA [143].
The OV is capable of selectively replicating in tumor cells, leading to their lysis. There is growing proof, in preclinical studies, on the combining synergistic effects of OV to several chemotherapies [144].
However, it is imperative to define the molecular mechanisms involved in the beneficial aspect of an individual therapy approach, despite the medicine adopted. This field is now translated in the clinical application for Chimeric Antigen Receptor (CAR) T-Cell Therapy. Moreover, microRNAs, a family of small noncoding RNAs implicated in the anti-cancer activity of many therapeutic agents, are shown to serve as attractive targets for the oncogene c-Myc-based combination therapy [145].
The mechanism of oxidative stress repeatedly described as a co-factor in cancer development could be a mechanism involved by cancer therapies. Many patients to decrease the side effect often need antioxidant supplementation to adjuvant therapy, which (i.e., Glutathione) [146], natural remedies [147], and other complementary and alternative medicines [148].
In this scenario, the genes encoding the familiar hallmarks of cancer must detect growth factor (GF) and GF receptors, apoptosis, multi-drug resistance, neovascularization, and invasiveness must be analyzed deeply. Also, the genetic predisposition related to factors promoting genome instability, inflammation, deregulation of metabolism and the immune system evasion/damaging must identify [149].
The ribosome-inactivating proteins (RIPs) are promising agents extracted from the plant with a complete damaging of the ribosomal activities [150].
Unlikely, no upgrading was seen for primary lymphoma central nervous system (PLCNS) in term of targeted therapy. The use of SMIs in PCNS and as preventing metastasis has failed [28]. Encouraging evidence supporting the addition rituximab to classical alkylating agents is growing, and a recent randomized trial (MATRix regimen) demonstrated a significantly better OS [151].
Based on this rationale, the oncologist should assess advantages and limits, regarding applicability and expenditure of the most fitting pharmacological approach to performing a customized therapy.
Finally, the Pharmacogenomic tests are mandatory for cancer targeted therapy; it can detect the variants that code mutant proteins markers, thus identifying tumors that may be susceptible to targeted therapy.