Abstract
Melanoma is the deadliest form of skin cancer and one of the most difficult cancers to treat. Overall, melanomas have more mutations than any other cancer type. Oncogenic mutations in c-KIT, NRAS and BRAF components of the MAPK pathway have been identified in nearly 90% of cutaneous melanoma and this information has been used to develop small molecules that inhibit their activity. Highly selective BRAF and MEK inhibitors have demonstrated impressive clinical results. However, the short duration of response, the acquired resistance in most cases and the toxicity issues support the rationale for drug combination approaches to improve the outcome of MAPK inhibitors, increase their efficacy, prevent and/or overcome resistance. This review discusses several promising rational combinatorial strategies investigated or could be investigated in clinical studies.
Incidence and mortality rates for melanomas, the most common form of cancer in people aged from 25 to 29, continue to rise faster than any other cancer type. Although melanoma accounts for only a small percentage of skin cancers, it is responsible for the majority of deaths of all skin cancers (1, 2). Increased understanding of the molecular events involved in melanoma development has led to the identification of novel targets and to the development of new targeted agents. Gene alterations identified in melanoma pointed to distinct molecular subsets of tumors with direct implications in therapeutic strategies. Among these, activating BRAF mutations occur in 50-60% of melanomas (V600E substitution represents about 90% of BRAF mutations), NRAS mutations in 20-30% of melanomas (mutually exclusive with BRAF mutation), KIT mutations and/or amplification in 39% of mucosal and 36% of acral melanomas (3, 4). These mutations opened new therapeutic perspectives targeting the MAPK pathway (hyperactivated in 90% of melanomas) with V600EBRAF, MEK or RTK inhibitors (5-7).
Vemurafenib and dabrafenib, specific inhibitors of the mutant BRAF (V600E), have been approved by the Food and Drug Administration (FDA) in 2011 and 2013 respectively, for the treatment of patients with unresectable or metastatic melanoma carrying the V600E mutation in BRAF. Furthermore, trametinib a selective inhibitor of MEK1/2 was approved for the same indication in 2013. The approval of these inhibitors was based on improved rates of overall and progression-free survival compared to chemotherapy in phase III clinical trials (6, 8, 9). Moreover, among new MEK inhibitors in clinical development, pimasertib and binimetinib (MEK162) have been recently reported to be particularly promising in the case of patients with mutant NRAS melanoma (10-12). Finally, the results of clinical trials evaluating RTK inhibitors sunitinib and imatinib in patients presenting mutated c-KIT have been published and showed an average response rate of 20% (7, 13).
Targeting MAPK pathway in melanoma with MAPK inhibitors has shown clinical benefit. However, the short duration of response and progression-free survival in patients due to resistance or to general toxicity indicate that combination therapeutic strategies are needed to enhance the effect of MAPK inhibitors. Therefore, efforts are ongoing to further understand resistance mechanisms and also to improve the outcome of MAPK inhibitors by rational use of combination therapy.
Current Combinations of Targeted Therapies and Perspectives
Cotargeting MAPK pathway at multiple levels. Regardless of the encouraging results obtained with the BRAF inhibitors dabrafenib or vemurafenib, the majority of patients develop resistance to BRAF inhibitors and relapse (14). In most cases, resistance is associated with reactivation of the MAPK pathway (15, 16). In addition, BRAF inhibitor-induced paradoxical activation of the MAPK pathway in RAS mutant cells and in wild-type BRAF cells, can result in secondary cancers, including cutaneous squamous-cell carcinoma (17-19). In this context, we reported the prominent role of cyclic AMP signaling pathway in the sensitivity of WTBRAF/WTNRAS melanoma cells to vemurafenib (20). We found that cells with low phospho-CRAF and high cAMP levels are sensitive to vemurafenib while in the resistant ones phospho-CRAF expression was high; and CRAF inhibition through cAMP stimulation overcame the resistance to the drug.
The MEK inhibitor trametinib, also improves the overall survival of patients with the BRAF V600E mutation compared with chemotherapy, and is not associated with paradoxical activation of the MAPK pathway (6). Further, the idea of combining a BRAF inhibitor with a MEK inhibitor has been tested for the treatment of BRAF mutated melanomas. Interestingly, this regimen blocks the MAPK pathway at two signaling points and can reduce the cutaneous toxicity related to the paradoxical reactivation of the MAPK pathway (21-23). Most importantly, phase III trials have shown that combined BRAF and MEK inhibition, compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects (24) (Table I). For instance, it was shown in two independent phase III trials, that the combination of dabrafenib and trametinib, compared with dabrafenib alone or the combination of vemurafenib plus cobimetinib, compared with vemurafenib alone significantly improved the progression-free survival, the overall survival and the objective response rate (complete plus partial) (24-26).
The rate of cutaneous squamous cell carcinoma highly decreased with the combination compared to the BRAF inhibitors alone (24-26). The combination of these inhibitors have been approved by the FDA in 2014 (dabrafenib and trametinib) and 2015 (vemurafenib and cobimetinib) for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. The combination of BRAF and MEK inhibition also showed a synergistic effect on the growth inhibition of NRAS mutant melanoma cells when there is a higher activity of the MAPK pathway and dependence of proliferation and survival on this pathway (27). Inhibition of ERK1/2 is also a promising strategy in melanoma. SCH772984 is a new selective inhibitor of ERK1/2 that has demonstrated antitumor activity in preclinical studies, against BRAF mutant, NRAS mutant and wild-type melanoma (28). Other selective ERK1/2 inhibitors as GDC-0994 are currently ongoing clinical trials as single agent (NCT01875705) or in combination with MEK inhibitors (NCT02457793) (Table I). Consequently, these findings provide a rationale for cotargeting MAPK pathway at multiple nodes (Figure 1) and suggest that this therapeutic strategy is a more effective one.
Co-targeting of MAPK and PI3K/AKT signaling pathways. PI3K/AKT pathway is frequently activated in melanoma. Activating mutation of c-KIT and NRAS can lead to constitutive activation of PI3K-AKT pathways (29, 30). In BRAF mutant melanoma, we showed that PI3K/AKT activation is associated with intrinsic and acquired resistance to BRAF inhibition (31).
Constitutive activation of PI3K/AKT pathway is due to multiple mechanisms (15, 32-34) including the loss of the tumor suppressor PTEN (20-30% of melanomas) that confers resistance to MAPK inhibition in melanoma (35-37). Therefore, acquired and innate oncogenic alteration in the PI3K/AKT signaling can explain the inefficiency of single pathway inhibition and the rationale for the concurrent targeting of both MAPK and PI3K/AKT pathways (Figure 1) to counteract resistance and obtain beneficial long-term clinical effects. Several studies have demonstrated antitumor activity and pointed out synergistic effect of cotargeting MAPK and PI3K/AKT pathways in BRAF and NRAS mutant melanomas (22, 24, 31, 38-40).
Otherwise, clinical studies have investigated the combination of MAPK and PI3K/AKT inhibitors in melanoma and other solid tumors (Table I). For instance, phase lb combination trial of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, was investigated in patients with locally advanced or metastatic solid tumors (NCT01390818). The combination of BYL719 (PI3K inhibitor) and binimetinib (MEK inhibitor) was studied in patients with advanced solid tumors (NCT01449058). Also, a phase I trial of BKM120 (PI3K inhibitor) combined with vemurafenib was also evaluated in V600E/KBRAF mutant advanced melanoma. Preliminary data show that these combinations are tolerated and active. However, data presented to date have only shown modest clinical activity of the combination. The efficiency of dual targeting could be increased by optimal dosing/timing schedules, or enriching the patients with predictive factors. Co-targeting of MAPK and p53 pathways. As a guardian of the genome, p53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis. In many tumors, the TP53 gene itself is mutated disabling its tumor suppressor activity. In melanoma, p53 is mutated in only 17% of cutaneous melanoma and in 8-10% of acral and mucosal melanomas (4); but its function is frequently attenuated by a variety of mechanisms, including increased expression of MDM2 (41) and/or MDM4 (42). Additionally, p53 function is compromised by deletions in the CDKN2A locus, which inactivates both p14ARF and p16INK4a in about 50% of melanomas (43). Increasing evidence supports a role for p53 in BRAF and NRAS driven melanoma progression in mice (44, 45) and zebrafish (46). Thus, p53 represents an important therapeutic target for melanoma. In an effort to reactivate p53, two strategies have been employed (Figure 1).
Selected clinical trials of combined strategies in melanoma.
The first involves increasing wild-type p53 levels by interfering with the MDM2/4 mediated proteasomal degradation of p53 using antagonists that inhibit MDM2/MDM4-p53 interactions. Combining the antagonist of the MDM2–p53 interaction, Nutlin3, with MAPK inhibitors suppresses melanoma growth and potentiates MAPK inhibition (47, 48). Restoring the apoptotic function of p53 by inhibiting MDM2 and iASPP cooperates with V600EBRAF inhibition to suppress human melanoma cell growth both in vitro and in vivo (49). Further, the combination of pimasertib (MEK inhibitor) with another antagonist of MDM2 (SAR405838) was investigated in phase I trial in patients with solid tumors (NCT01985191) (Table I). In cells where MDM2 is low, MDM4 could be the principle regulator of p53 (50). It has been shown that MDM4 is overexpressed in about 65% of human melanomas and that its inhibition by SAH-p53-8 affects the growth of melanoma cells that have acquired resistance to BRAF inhibitors and synergizes with BRAF inhibitors to kill BRAF mutant cells (50).
The second strategy used to re-activate p53, consists of targeting p53 directly using small molecules as PRIMA-1 (stands for “p53 Reactivation and Induction of Massive Apoptosis”) and its methylated form PRIMA-1Met (APR-246) that have the ability to convert mutant and wild-type inactive p53 to an active conformation, restoring DNA binding and transcriptional activity (51, 52). PRIMA-1/PRIMA-1Met alone or in combination with chemotherapy has been shown to have good efficacy against various types of cancers, such as leukemia (53), breast (54, 55), thyroid (56), pancreatic (57), ovarian (58), prostate (59), colorectal (60) and non-small lung cancers (61). The safety of APR-246/PRIMA-1Met has recently been tested in a phase I clinical trial (62) and after positive data obtained from a clinical phase I/II study with APR-246, a global pivotal phase III study in high grade serous ovarian cancer (HGSOC) patients is also intended for PRIMA-1Met. In melanoma, we evaluated recently the potential of combining oncogenic BRAF inhibition with direct pharmacological reactivation of p53 (63). We found that the p53 activator (PRIMA-1Met) synergized with the BRAF inhibitor vemurafenib to induce apoptosis and suppress proliferation in vitro and to inhibit tumor growth of BRAF mutated melanoma cells in vivo. Importantly, this drug combination decreased the viability of both vemurafenib-sensitive and resistant melanoma cells irrespectively of the p53 status. Thus, PRIMA-1Met through its ability to directly reactivate p53 regardless of the mechanism causing its deactivation, and thereby dampen PI3K signalling, sensitizes V600E/KBRAF-positive melanoma to BRAF inhibitors. This work has also been the rationale for an academic phase I/II clinical trial using this original combination.
Nevertheless, the anti-melanoma potential of p53 reactivation was also evaluated in combination with a MEK inhibitor in NRAS mutant melanoma cells and our preliminary results demonstrate a strong synergistic effect of this combination (data not published).
Taken together, these data suggest that the combination of MAPK inhibitors with additional pharmacological agents like a p53 reactivator, converting their predominantly cytostatic to a cytotoxic effect, could improve their efficacy. Co-targeting MAPK and CDK/4. Cyclin-dependent kinases (CDK) are a family of serine/threonine kinases that drive cycle progression, control transcriptional processes, DNA replication and cell division (64, 65). The synthesis of cyclins and their bindings to CDK are specific of the stages of the cell cycle and regulate CDK activity (64, 65). The activity of CDK is also regulated by the families of the inhibitory proteins of CDK including p15, p16INK4a, p18, p21 and p27. The p16INK4a protein binds to CDK4/6 inhibiting interaction with cyclins D, which would otherwise promote cell-cycle progression by inhibiting retinoblastoma (RB) protein (64, 65). The p16/cyclin D/CDK4/6/RB protein pathway (CDK4 pathway) is dysregulated in 90% of melanomas (66, 67). Furthermore, activation of the CDK4 pathway cooperates with mutant BRAF or NRAS in transformation of melanocytes (68, 69). MAPK pathway also enhances CDK4 signaling through increasing cyclin D1 expression. Amplification of cyclin D1 is detected in about 17% of BRAF V600E-mutated human metastatic melanomas, and, when it is combined with dysregulation of CDK4, it contributes to the resistance to BRAF inhibitor in such mutant melanoma cells (70). Thus, the emerging CDK4 as an important target in melanoma and other cancers led to the development of small-molecule inhibitors of the kinase activity of CDK4 (Figure 1). CDK4/6 inhibitors have been tested as single agents or in combination. Studies were focusing on evaluating the rational combination of CDK4/6 inhibitors with MAPK inhibitors (Table I). A study have demonstrated that dual inhibition of CDK2 and CDK4 enhanced response to BRAF and MEK inhibitors in melanoma cells in vitro and in vivo (71). Further, the combination of CDK4-inhibitor palbociclib with trametinib (MEK inhibitor) has shown a synergistic effect in NRAS-mutant melanoma (72). The CDK4/6 inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) have been evaluated in several phase I-II trials in combination with MEK and BRAF inhibitors (NCT02065063, NCT02202200, NCT01777776, NCT01781572 and NCT01820364). The combination of the CDK4/6 inhibitor ribociclib (LEE011) with the MEK1/2 inhibitor binimetinib (MEK162) has also shown an activity in patients with NRAS mutant melanoma (NCT01719380). The activity of CDK4/6 inhibitors appears to be greater where there is higher activity of CDK4 pathway (mutant or amplified CDK4, gains of cyclin D1) and inactivation of RB protein appears to predict resistance to CDK4 and CDK6 inhibitors (73).
Multimodality Treatments and Future Directions
Immunotherapy and targeted-therapy combinations. Another modality in melanoma treatment involves the use of immunotherapy. The immune checkpoint inhibitors, anti CTLA-4 (ipilimumab) and anti-PD1/PDL1 antibodies (pembrolizumab, lambrolizumab, nivolumab, MPDL3280) (Figure 2) have made revolutionary immunotherapeutic advances and have demonstrated clinical activity in melanoma (23, 74-78). In addition to their use as monotherapies, anti-CTLA-4 and anti-PD1/PDL1 are now being combined in clinical trials, and have shown impressive response rates (Table I). Indeed, concurrent or sequential combination of anti-CTLA-4 and anti-PD-1 achieved an objective response rate (ORR) of 40% (ranging from 21 to 53%, n=52). Further, 31% of the patients treated with the concomitant combination had a reduction in disease burden of at least 80% (NCT01024231).
The discovery of either molecularly effective targeted therapies or immunotherapies has led to dramatic improvements to the standard-of-care treatment of melanoma. Treatment with targeted therapy yields rapid but non-durable responses in most patients. Conversely, treatment with immune checkpoint blockade can produce durable but often delayed responses. Thus, dual immune and molecular therapy together can lead to early and robust antitumor responses with long-term benefit for patients.
Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy (Figure 2). Indeed, it was suggested that oncogenic BRAF can lead to a tumoral immune escape (79, 80). Furthermore, treatment with MAPK inhibitors is associated with enhanced expression of melanocytic antigens, antigen recognition by T cells, and influx of cytotoxic T lymphocytes (CTLs) (81-83). Also, it was suggested that resistance to BRAF inhibitor leads to increased expression of PD-L1 in melanoma cells, and MEK inhibition shows dual therapeutic effects with simultaneous suppression of PD-L1 expression and induction of apoptosis (84). These findings offer compelling evidence for the development of combined targeted and immune therapies, and indicate immune checkpoint blockade may enhance antitumoral response when combined with MAPK inhibition. An ongoing targeted and immunotherapy trial uses dabrafenib with or without trametinib combined with ipilimumab in patients with BRAF V600E/K-mutated metastatic melanoma (NCT01767454). Other clinical studies have been planned or are underway (Table I), each with varying dose levels and schedules of combination therapy administration (NCT01656642, NCT02130466 and NCT02027961). These trials will help in understanding the profile of toxicity, the optimal timing and sequence of the combination therapy profile. It will also provide preliminary efficacy data of various combinations and will help to guide optimal management of melanoma patients.
Combining MAPK inhibition and radiotherapy. Melanoma is commonly regarded as a radioresistant tumor entity, although adjuvant radiotherapy plays a role in treatment regimens for patients suffering from advanced disease by reducing the risk of local and metastatic tumor relapse (76). Moreover, radiation therapy is often used to relieve symptoms caused by the spread of the melanoma, especially to the brain or bones. Radiation, like a variety of other cellular stress factors, can activate or down-regulate multiple signaling pathways, leading to either increased cell death or increased cell proliferation. Modulation of the signaling process however, depends on the cell type, radiation dose, and culture conditions (85). MAPK signaling is known to potentially influence tumor cell radiosensitivity because of their activity associated with radiation-induced DNA damage response.
ERK is activated very rapidly in tumor cells in response to radiation (86). Mutations occurring in the RAS/RAF pathway further result in enhanced tumor cell proliferation and survival after irradiation (87, 88).
Interestingly, inhibition of BRAF in melanoma brain metastasis with activating BRAF mutations results in sensitization to ionizing radiation (89, 90). The combination of BRAF inhibitor dabrafenib with stereotactic radiosurgery in V600EBRAF melanoma brain metastases is investigated in a phase 2 prospective trial (NCT01721603).
The MEK inhibitor trametinib radiosensitizes RAS-/RAF-mutated melanoma cells by inducing prolonged G1 arrest and premature senescence. In this pre-clinical study Schick et al. demonstrated that combining trametinib and radiotherapy is well tolerated and reduces tumor growth in vivo (91).
Furthermore, Eder S et al. (92) have shown that pharmacological interference with MAPK signaling increases vulnerability of NRAS-mutant melanoma cells to ionizing radiation and point towards a possible use for combined MEK inhibition and localized radiation therapy of malignant melanoma in the NRAS-mutant setting where BRAF inhibitors offer no clinical benefit. Additionally, RTKi potentiate the effect of radiotherapy in cancer (93). These observations suggest that signaling through the MAPK pathway is important in radiation response and radiation resistance, and inhibition of this cascade may be an attractive means to sensitize tumor cells to ionizing radiation.
Regarding the rationale behind combined targeted therapy and immunotherapy and given the potential synergy between radiotherapy and targeted therapy on one hand and immunotherapy on the other, adding radiotherapy to the dual therapies (imuno- and targeted- therapies) could also be an option that may lead to improvements in locoregional and distant tumor control and would be effective in the cases of brain metastasis.
P53 reactivation and radiotherapy. P53 pathway is known to be implicated in the regulation of the response to ionizing radiations in tumor cells (94-96). Radiation will induce ataxia telangiectasia (ATM) mutated and other kinases that results in the phosphorylation and activation of p53 (Figure 2) (97).
Several studies have reported synergistic suppressive effects of combining TP53 gene transfer treatment with x-ray radiation on various cancer cells including head and neck, glioblastoma, colorectal, cervical, lung, and malignant glioma cell lines (98-103). In murine melanoma cells, Duan X. et al. (104) found that heavy-ion radiation combined with TP53 gene transfer induced apoptosis. Furthermore, the effects of wild type p53 activation via MDM2 inhibition in combination with radiation have been examined in lung and prostate cancers (95, 105, 106). Recently, a study by Feng F. et al. (107) showed that MDM2 inhibition combined with MI-219 results in p53-dependent sensitization of prostate cancer cells to radiation. Another study by William J. et al. (108) reported that intrinsic radiosensitivity of 39 human tumor cell lines segregated into distinct genotype-dependent radiosensitivity groups that are associated with wild-type TP53 and mutant TP53, showing that wild-type TP53 cells are significantly more sensitive than mutated ones.
Key melanoma signaling pathways involved in proliferation and survival and selected therapeutic agents that target each of these pathways. MAPK pathway is the central pathway in melanoma, activated in nearly 90% of cases due to oncogenic mutations in c-KIT, NRAS and BRAF. In parallel, PI3K/AKT pathway is also activated in melanoma due to loss of function of PTEN or activation of AKT. The pro-apoptotic p53 pathway is inactivated in the majority of the cases in melanoma due to overexpression of its negative regulators (MDM2/MDM4). The p16/cyclin D/CDK4/6 - retinoblastoma protein (RB1) pathway (CDK4 pathway) is also dysregulated in melanoma. Numbers in the red circles (1-9, 11) and green circle (10) represent respectively the mechanism of action of inhibitors and activators used to modulate these pathways with a high therapeutic potential.
Multimodality treatments and future directions. Schematic representation of the main reasons behind the rationale to use combinatorial approaches including targeted therapies, immunotherapy and radiotherapy. New immunotherapeutic agents in melanoma involve immune checkpoint inhibitors anti-CTLA-4 and anti-PD1/PDL1 antibodies. (A) Upon T cell activation via T cell receptor (TCR) engagement by MHC-peptide complex between APC and T cells, CTLA-4 competitively blocks the binding of costimulatory ligands CD80 and CD86 to CD28. Antibodies against CTLA-4 (ipilimumab) act at the initiation of the immune response by maintaining T cell activation. (B) In metastatic melanoma, the interaction of PD-L1 expressed by melanoma cells with PD-1 induces T cell suppression. Anti-PD-1 antibodies induce T cell reactivation by preventing binding of PD-1 with its ligands. (C) Activation of dendritic cells and up-regulation of MAA (melanoma associated antigens) by BRAF inhibition and suppression of PD-L1 expression by MEK inhibition offer compelling rationale to combine targeted and immune therapies. (D) Radiotherapy can induce the activation of p53 via ATM. Targeting MAPK and p53 can sensitize melanoma cells to radiation. (E) Radiotherapy combined with anti-PD-L1 up-regulates MHC, and increases tumor cell susceptibility to immune-mediated cell death.
Unfortunately, only a few observations are available for the impact of p53 targeting on radiotherapy in melanoma.
Immunotherapy and radiotherapy combination. Investigations into the interaction between radiotherapy and the host immune system have elucidated new mechanisms that can potentially be exploited to improve the efficacy of radiotherapy (109).
The combination of local radiotherapy and immune-modulation can augment local tumor control and cause distant antitumor effects (abscopal), increasing tumor-antigen release and antigen-presenting cell (APC) cross-presentation, improving dendritic cell (DC) function, and enhancing T cell priming (110-113) (Figure 2). On the other hand, ionizing radiation can also generate chemotactic signals that recruit several myeloid-cell types with distinct roles in T cell suppression (114-116).
The major clinical successes in the nascent field of radioimmunomodulation are the result of the advent of immune-checkpoint inhibitors. Inhibitors of the CTLA-4 pathway, such as ipilimumab, have shown encouraging results in the treatment of patients with cancer. CTLA-4 functions as an immunosuppressor by increasing the signal intensity required for CD8+ T cells to engage target cells in the tumors (117).
A retrospective study where patients with advanced melanoma were grouped into those who had received concurrent radiotherapy while on ipilimumab (Ipi-RT), and those who did not, showed an improved survival and complete response rates in patients treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. Also, toxicities were not increased in the Ipi-RT group compared with ipilimumab alone (118).
In addition, inhibition of the PD-1/PD-L1 pathway on T cells has been associated with a potent antitumor activity in mouse tumor models and in clinical trials (71, 115-117).
A preliminary preclinical report has indicated that radiotherapy combined with anti-PD-1 antibody treatment can result in primary tumor control (119). More recent data from the same group indicated that this therapy combination results in induction of endogenous antigen-specific immune responses, resulting in improved local control in single tumor models of melanoma or breast carcinoma (112).
Thus, current evidence indicates that enhancing innate and adaptive immunity by combining radiotherapy and immunotherapy is a crucial strategy to improve patient survival.
Conclusion
Melanoma treatment has witnessed dramatic progress and several revolutionary therapeutic advances with the discovery of molecularly-effective targeted therapies (BRAF and MEK inhibitors) and immunotherapies (anti-CTLA-4 and anti-PD1/PDL1 antibodies) which significantly improve the standard-of-care treatment of melanoma. Monotherapy is unlikely to yield a long-term benefit due to drug resistance. Thus, rationale-based combinatorial strategies are the key to overcome resistance and obtain a long-term response. Ongoing studies are investigating many combinatorial approaches but the key issues addressed are the ideal timing and sequences of combination regimens that can give the higher efficacy, durable response and lower toxicity.
Acknowledgements
This work has been supported by a grant from “Les Amis de l'Institut J. Bordet” and “Fondation contre le Cancer”, Belgium. AN was a recipient of the “BRIC” grant, Université Libre de Bruxelles.
Footnotes
↵* These Authors contributed equally to this study.
This article is freely accessible online.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received April 28, 2017.
- Revision received May 18, 2017.
- Accepted May 19, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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