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Kinase Inhibitors in the Treatment of Ovarian Cancer: Comparison
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Please note this is a comparison between Version 2 by Amina Yu and Version 3 by Amina Yu.

Ovarian cancer is the deadliest gynecological cancer, the high-grade serous ovarian carcinoma (HGSC) being its most common and most aggressive form. Despite the latest therapeutical advancements following the introduction of vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors and poly-ADP-ribose-polymerase (PARP) inhibitors to supplement the standard platinum- and taxane-based chemotherapy, the expected overall survival of HGSC patients has not improved significantly from the five-year rate of 42%. This calls for the development and testing of more efficient treatment options. Many oncogenic kinase-signaling pathways are dysregulated in HGSC. Since small-molecule kinase inhibitors have revolutionized the treatment of many solid cancers due to the generality of the increased activation of protein kinases in carcinomas, it is reasonable to evaluate their potential against HGSC.

  • clinical trials
  • high-grade serous ovarian carcinoma
  • kinase inhibitor
  • preclinical studies
  • ovarian cancer xenografts

1. Background

1.1. Epithelial- and High Grade Serous Ovarian Carcinoma

Ovarian cancer is usually diagnosed at an advanced stage due to the late onset of symptoms, which makes its curative care challenging. Almost 314,000 women are diagnosed worldwide with ovarian cancer and more than 200,000 die from the disease every year (https://www.wcrf.org/cancer-trends/ovarian-cancer-statistics/; accessed on 1 October 2022). About 90% of ovarian cancers are of epithelial origin and are thus called epithelial ovarian cancers (EOC). There are several ovarian cancer subtypes, with up to 80% of patients diagnosed with an EOC subtype of ovarian high-grade serous carcinoma (HGSC). The current EOC standard-of-care (SOC) is surgery combined with a platinum and taxane-based chemotherapy. About 80% of patients with advanced cancer respond well to the primary treatment, but unfortunately, almost all of them will relapse and eventually develop a resistant disease [1]. This leads to a short life expectancy, with an overall 5-year survival rate of 42% [2]. The relapsed chemo-resistant HGSC is very aggressive, fast-growing and invasive [3]. Ovarian cancer deaths are expected to increase globally up to 67% by the year 2035, due to an overall increase of the ageing population [4], if no progress in treatment modalities is achieved. Herein, the focus will concentrate on HGSC and on the recent research concerning its potential treatment with small-molecule kinase inhibitors.

1.2. Development of the Current Treatment

The standard first-line treatment of HGSC is cytoreductive surgery combined with platinum and taxane-based chemotherapy. Whether the surgery is completed before or after the chemotherapy depends on the extent of the cancer spread and general health of the patient. The use of platinum compounds as a chemotherapy of ovarian cancer was already introduced about 30 years ago: firstly, cisplatin as a monotreatment [5], and two decades later in combination with taxane [6][7]. While platinum compounds cause DNA crosslinking that modify DNA structure and inhibit its synthesis, taxane compounds prevent microtubule depolymerization, resulting in the inhibition of mitosis and induction of programmed cell death of dividing cells. In the current clinical practice, carboplatin has often replaced cisplatin due to its lower toxicity.
The first targeted treatment of HGSC was the humanized monoclonal antibody bevacizumab that inhibits the binding of the vascular endothelial growth factor-ligand (VEGF) to the VEGF receptor (VEGFR) [8]. Inhibition of VEGF pathway can alternatively be achieved by VEGFR tyrosine kinase inhibitors, such as sorafenib and pazopanib [9]. VEGF pathway inhibition targets tumor vascularization, which is an efficient method to suppress tumor growth and invasion in many cancers, including ovarian cancer, due to its ability to interfere with the high oxygen and nutrition demands of tumors.
Recently, PARP inhibitors, such as olaparib, niraparib and rucaparib, have been introduced as targeted therapy in addition to VEGFR inhibition. PARP1 and PARP2 are needed for the repair of damaged single-stranded DNA. Inhibition of DNA repair with PARP inhibitors induces programmed cell death in cancer cells [8][9]. PARP inhibitors are mostly recommended for relapsed, platinum-sensitive HGSC and are efficient for breast cancer gene type 1 and type 2 (BRCA)1/2-deficient (germline and somatic) and/or homologous recombination deficient (HRD) tumors, which are expected to cover 20% and 50% of HGSC, respectively.
Both targeted therapy approaches have mainly been used as a maintenance therapy for their ability to slow down tumor growth and metastatic spreading, and they can be administered in combination with chemotherapy and to patients with platinum-sensitive tumors. Trials combining PARP and VEGF inhibition have turned out promising, indicating that their dual targeting could even benefit patients without HRD tumors [10]. Such a synergistic combinatorial effect is likely based on multiple mechanisms, which include the downregulation of homologous recombination regulators BRCA1/2 and a DNA repair protein RAD51 via VEGFR inhibition-induced hypoxia together with potential BRCA downregulation-induced restoration of chemosensitivity [11]. More details about the current treatment recommendations of Food and Drug Administration (FDA), including some more rare and special cases, can be found elsewhere (https://www.cancer.org/content/dam/CRC/PDF/Public/8776.00.pdf; accessed on 1 October 2022).

1.3. Challenges in Developing New Treatments

Most targeted cancer treatments are classically designed against growth factors, receptors, cell cycle regulators or other druggable members of signaling pathways that harbor constitutively activated mutations in genes that drive the aberrant growth of cancer cells. Most of these are oncogenes, and their targeting is based on the observation that the cancer cells expressing them exhibit so-called “oncogene addiction”, which manifests in a sensitivity toward a drug or a treatment that targets that particular oncogene or the main signaling pathway it activates [12]. In this respect, HGSC is special since it lacks known driver oncogenes. Instead, a typical driver mutation for HGSC is a loss-of-function mutation of the tumor suppressor p53 (TP53), whose prevalence is close to 100% [13]. Although many experimental approaches have been developed [14], the clinical challenge for the efficient restoration of mutated, inactivated TP53 still remains.
Immunotherapy has proven very promising for the treatment of many solid tumor cancers. However, it has turned out to be less efficient and more disappointing in the treatment of HGSC. Experimental immunotherapeutic trials have recorded only 4–15% response rates upon targeting the programmed death protein (PD-1) or its ligand (PD-L1) [15], which is poorly expressed in HGSC in general. Of HGSC tumors, generally those that show higher expression of PD-L1 are the BRCA1/2-deficient ones, which also typically exhibit higher mutation rates than non-BRCA1/2-deficient tumors, and, in this sense, are also more immunogenic. Disappointingly, first trials considering this have shown that BRCA-deficient tumors did not demonstrate any better clinical response to PD-1/PD-L1 inhibition either [16]. Despite these obstacles, immunotherapy is still considered a valid possibility for the treatment of HGSC, since ovarian tumors expressing high numbers of T-cells are generally associated with a longer survival, while those showing signs of activated immune evasion mechanisms are associated with a poor survival [15]. Thus, currently, several trials are exploring immunotherapy, namely PD-1/PD-L1 inhibition, in combination with VEGF/VEGFR or PARP inhibition.

1.4. Kinase Inhibitors as Cancer Treatments in General

Deregulated protein kinase signaling is one of the hallmarks of cancer. Moreover, protein kinase families are structurally and functionally similar, making it relatively easy to design and synthesize inhibitors for them. It is, therefore, not surprising that the development of small-molecule kinase inhibitors has revolutionized the cancer treatments [17]. Human kinome comprises 538 kinases and by the year of 2021, 76 kinase inhibitors have received FDA approval as anti-cancer agents (https://www.ppu.mrc.ac.uk/list-clinically-approved-kinase-inhibitors; accessed on 1 October 2022). None of these have been approved for the treatment of HGSC, but several have already been or are currently under evaluation as mono- or combinational therapies for HGSC.

2. Current Progress with Small-Molecule Kinase Inhibitors as Targeted Treatment for HGSC

2.1. Many Less and Few More Promising Attempts

The critical cellular processes that are needed for cancer progression, such as increased cell growth and survival, tumor invasion and metastasis formation are regulated by receptor tyrosine kinases (RTKs) via signal transduction from extracellular ligands to intracellular signaling pathways. These ligands include epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and insulin. The binding of an extracellular ligand to its respective RTK results in receptor aggregation and conformational changes, followed by the phosphorylation of multiple tyrosine residues in its kinase domain and in its C-terminal intracellular domain, leading to its activation. This, in turn, initiates complex intracellular signaling cascades that modulate such diverse processes as proliferation, cell migration, survival, and cell growth. Some of these oncogenic signaling pathways are activated in HGSC [18][19]. Due to high intra and inter heterogeneous nature of ovarian cancer, optimization is needed for the incorporation of kinase inhibitors into clinical practice.

2.2. Targeting Receptor Tyrosine Kinases (RTKs)

Since the dysregulation of RTKs is frequent in EOC, and given the pressing need for novel, efficient targeted therapeutics, both single- and multi-kinase inhibitors have attracted significant attention as potential treatments for advanced metastatic ovarian carcinomas.

2.2.1. Aiming at Upregulated ErbB Family Receptors

Epidermal growth factor (ErbB) family of receptor TKs consists of epidermal growth factor receptor (EGFR/ErbB1), ErbB2 (human epidermal growth factor receptor 2, HER2) and ErbB3-4. Immunohistochemical studies indicate that 30–70% of HGSC tumors have increased EGFR expression [20][21], and high EGFR expression has been linked to chemoresistance and poor prognosis [22]. Although small-molecule kinase inhibitors have shown significant clinical benefits in, for example, lung cancers expressing activated EGFR, using these agents as monotherapies had shown a very little effect for HGSC [23]. Consequently, the combination of EGFR inhibitor gefitinib with topoisomerase inhibitor topotecan in HGSC patients did not show sufficient clinical activity either, despite the enrollment of EGFR-positive patients for the trial [24].
Both ErbB2/HER2 overexpression and ERBB2 gene amplification have been reported in ovarian cancers, and a study on HER2 expression comparing both fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) staining methods using advanced ovarian tumors from 320 patients indicated that 7% of them were HER2-positive (HER2 3+) [25]. In most studies, elevated HER2-expression has not been associated with prognosis, survival, or treatment response in ovarian cancers, although in some cases, the introduction of HER2 inhibition as antibody-based trastuzumab treatment to the treatment plan has proven efficient [26]. The vast majority of small TKIs targeting either HER2 or both EGFR/HER2 have already been tested in preclinical or phase I trials [27]. Research on the expression of ErbB3 and ErbB4 have not shown significant correlations with disease outcome or clinical variables in EOC either [28]. Despite the reported ErbB4 pathway activation in EOC [29], the use of ErbB4-targeted inhibitors has not reached the level of clinical trials.

2.2.2. Exploiting High Angiogenic Drive

The formation of new blood vessels is essential to sustain continuous tumor growth and metastasis formation. Specifically in EOC, earlier studies have shown high levels of VEGF in ascites, suggesting that peritoneal cavity might be characterized by intense angiogenic activity [30]. Given the fundamental role of angiogenesis in tumor development and the established association of VEGF upregulation with survival, VEGFA-selective antibody bevacizumab was approved for both front-line and maintenance therapy for ovarian cancer [31][32]. Other VEGF-blocking agents, including TKIs, have been investigated in clinical trials, and they seem promising for patients with advanced, relapsed disease. The combinations of selective VEGFR-inhibitors apatinib or cediranib with platinum-based chemotherapy have showed activity and manageable toxicities in several clinical trials [33][34], suggesting that such a treatment combination has potential benefits through therapeutic synergy. Despite the promising results with VEGF TKIs, they have not replaced bevacizumab as a VEGF-targeting approved agent as a first-line treatment for advanced EOC. In the view of abnormal levels of KIT and PDGFR expression found in advanced ovarian cancers, several clinical trials have been conducted with imatinib, which targets both of them [35][36][37][38]. However, imatinib did not show significant clinical activity, neither as a single agent, nor in combination with chemotherapy, nor could the expression levels of PDGFR and KIT predict the treatment response.

2.2.3. Exploring Oncogenic Potential of FGFR

Tyrosine kinase receptors FGFR1-4 (FGFRs) are involved in cell survival, migration, angiogenesis, and carcinogenesis. Both mutations and amplifications in FGFRs are frequent in various cancers, and they are potential ‘driver’ mutations, with FGFR gain-of-function aberrations being strongly related to treatment sensitivity and disease outcome in many cancers [39]. Aberrations in the FGF/FGFR pathway have also been reported in HGSC [39][40][41], with the majority being amplifications or activating mutations, which suggests that FGFR inhibition could be a beneficial therapeutic option for it. The therapeutical targeting of FGFR can be approached with FGFR-selective or multi-targeted TKIs, with the latter ones being already widely involved in clinical trials on ovarian cancer patients.

2.2.4. Probing the Complex Network of IGF Signaling

Insulin-like growth factor (IGF) signaling is needed for the maintenance of healthy ovarian tissue [42]. Hence, the dysregulation of this pathway has been acknowledged in studies involving HGSC [43][44][45]. The insulin-like growth factors IGF1/IGF2, along with the IGF1 receptor IGF1R, play a pivotal role in regulating cell growth, and specifically IGF1R signaling predominates in proliferating cells, being possibly influenced by p53 status. However, early preclinical studies targeting IGF1R by monoclonal antibodies (mABs) as a monotreatment resulted in a minimal benefit [46], as did the studies using monoclonal antibodies (mABs) in combination with standard chemotherapy or PI3K-AKT/NOTCH/mTOR inhibitors (NCT00718523, terminated prematurely).
The possible reasons for failures of IGF-targeting strategies in the clinical trials of HGSC patients can be rooted to the complexity of IGF signaling. Firstly, to target IGF signaling effectively, one needs to impair the ligand-induced activation of IGF1R while maintaining the control for the insulin-based activation of the insulin receptor (IR) [47]. Secondly, an inefficient targeting strategy may be due to the compensatory signaling by other RTKs, for example, by IR or ERBB family receptors operating outside of the IGF system. Finally, in addition to these direct RTK interactions, the blocking of the IGF1R pathway may be recompensated by the upregulation of downstream signaling converged via canonical PI3K-AKT and extracellular signal-regulated kinase (ERK) cascades [48].

2.3. Targeting Intracellular Signaling Cascades

The activation of AKT-PI3K and rapidly accelerated fibrosarcoma and mitogen-activated protein kinase (RAF-MEK) pathways are common in many cancers and can occur by aberrations in upstream signaling molecules, such as RTKs, or via mutations in intrinsic members of the two pathways [49]. The dysregulation of components of these cascades have a prominent effect on cell proliferation, differentiation, and survival. Furthermore, since these pathways are implicated in the resistance and sensitivity to chemotherapy, enormous efforts have been applied to develop inhibitors, specifically targeting the critical components of these pathways, with the aim to increase patient survival and improve response to the standard cancer treatments [49].

2.3.1. PI3K-AKT-mTOR Arm

The PI3K-AKT cascade is one of the best-characterized and most critical signaling pathways with regards to the transduction of anti-apoptotic signals in cell survival, and it is also one of the most frequently aberrated pathways in a range of tumors, including HGSC [50][51][52][53], with PIK3CA being increased in copy numbers in 40% and mutated in 12% of HGSC [51][54]. Inhibitors targeting this cascade can be categorized into four groups: PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K and mTOR inhibitors. Despite the clinical trials established for each of these four groups and several PI3K inhibitors being approved by FDA for other cancers, none of the compounds have yet progressed to clinical use for ovarian cancers. Dual PI3K-mTOR inhibitors have not yet advanced beyond phase I in any cancer either, mostly due to the compromised safety or frequent adverse events [55][56][57][58][59].

2.3.2. RAS-RAF-MEK-ERK (MAPK) Arm

The RAS-RAF-MEK-ERK signaling pathway, activated mainly via the ligand stimulation of RTKs, plays a vital role in the diverse cellular processes. Its dysregulation enhances tumorigenesis, impacting not only cell proliferation, but also cell division and survival [60]. The aberrations in the kinases of RAS-RAF-MEK-ERK pathway are frequently observed in various malignancies [61][62][63] including HGSC, where dysregulated activity of this pathway was found in 30% of patients [64]. With regards to HGSC, predominantly MEK and, to a lesser extent, p38 MAPK-selective inhibitors have lately been in the focus of clinical trials phases I-III, but despite great hopes concerning established MEK inhibitors, such as trametinib and selumetinib, their potential usefulness was observed only in the low-grade serous ovarian cancer (LGSC) subtype [65][66], failing to show utility beyond preclinical studies in HGSC [67].
P38 MAPK is another key member of the RAS-RAF-MEK-ERK signaling cascade, which is activated in tumors in response to radiotherapy and chemotherapy. Ralimetinib, a highly potent and selective inhibitor of p38 MAPK, has demonstrated in vivo efficacy in preclinical studies of diverse range of cancer xenografts and cell lines [68][69][70]. This success first inspired a phase I trial in patients with metastatic breast cancer [71], followed by its clinical evaluation conducted in patients with recurrent platinum-sensitive HGSC [72]. However, only a modest improvement in progression-free survival (PFS) was observed [72].

2.3.3. Targeting Cell-Cycle Machinery

Cell-cycle machinery is a tightly regulated series of events enabling cell division. The progression through each stage of the cell-cycle is driven by the proteins called cyclins and their catalytic partners, the cyclin-dependent kinase (CDK) family of serine/threonine kinases. This progression is also strictly monitored at the specific positions known as cell-cycle checkpoints by several cell-cycle checkpoint kinases (CHK) [73]. Hence, it is not surprising that the activities of CDKs and CHKs, being frequent targets for dysregulation in cancer, have led toward the development of the pharmacological inhibitors.
With regards to HGSC, targeting cell-cycle proteins was deemed as a potential strategy, due to the frequent amplification of cyclin E1 (CCNE1) associated with resistance to platinum-based chemotherapy [74]. The aberrant expression of other cyclins, CDKs and CDK inhibitors, has been shown in multiple studies of HGSC [75], suggesting that inhibitors of CDK4/6 might be effective in these tumors. Cell-cycle checkpoint kinases CHK1 and CHK2 are two critical messengers of the genome integrity checkpoints, with CHK1 being especially of interest for the TP53-mutated HGSC tumors with a compromised G1 checkpoint [76]. The utility of CHK inhibitors is, however, limited due to the poor safety profile; for instance, cardiotoxicity, including myocardial infarction, has been associated with AZD7762 (CHK1/CHK2 inhibitor; [77]) and MK8776 (CHK1 inhibitor; [78]) in patients with advanced solid tumors.
Mitosis inhibitor protein (Wee1) kinase, phosphorylated and stabilized by CHK1, negatively regulates entry into mitosis at G2/M transition, and, similarly to CHK1, its role in cancer remains controversial. However, Wee1 is upregulated in several cancers, including glioblastoma, melanoma, breast cancer, and ovarian carcinomas, with the latter ones showing higher expression following exposure to chemotherapy [79]. In the preclinical studies, the Wee1 kinase inhibitor adavosertib improved the sensitivity of TP53-mutant cells to chemotherapy, which led to its evaluation in clinical trials in patients with TP53-mutant HGSC [80][81].
Although the therapeutic potential of cell cycle checkpoint kinases has been in the focus of clinical trials for several years, the development and utility of CHK inhibitors in clinical settings has progressed at a slower rate than for the CDK inhibitors. However, the dysregulated cell-cycle machinery remains an area of intense investigation in ovarian cancer and will hopefully yield new therapeutic modalities in the near future.

2.4. Kinase Inhibitors in Recently Concluded Clinical Trials—What Is Promising?

Forty published clinical studies are included in the final table, with most of them administering kinase inhibitors in combination with other drugs, such as the PARPi olaparib or standard chemotherapy. Twenty-five of the studies reported prolonged progression free survival (PFS) and/or clinical activity of the administered kinase inhibitor, but the conclusions were in general rather modest. One of the more positive studies was performed with apatinib combined with pegylated liposomal doxorubicin (PLD), where both PFS and the overall response rate (ORR) were significantly improved compared to PLD alone. However, the effect was not superior to treatment with PLD combined with bevacizumab [82]. The remaining 15 studies in the table found no effect or even disadvantage of the treatment. The latter was the case for pazopanib maintenance, which decreased OS and increased adverse events (AEs) [83], cabozantinib, which decreased OS, event-free survival (EFS) and showed worse ORR [84], and everolimus, which increased AEs [85].

2.4.1. Multi-Targeted Anti-Angiogenic TKIs

A plethora of phase II-III trials conducted on patients with advanced OVC utilized multi-targeted anti-angiogenic TKIs, such as nintedanib [86][87][88], famitinib [89], pazopanib [83][90][91], sorafenib [92], cabozantinib [84][93], lenvatinib [94], or sunitinib [95], either in combination with other anticancer drugs or as maintenance monotherapy. Even though the majority of these agents showed no additive toxicity, the results of the clinical efficacy of multi-targeted TKIs were vastly discouraging when compared to a standard-of-care platinum-based therapy or maintenance therapy with bevacizumab.
The largest study in the table is a double-blind phase III RCT, including 1366 OVC patients treated with a combination of nintedanib and chemotherapy. This results comprise two publications: one reporting the primary outcome, PFS [88], and another reporting the secondary outcome, OS [87]. It is found that while the combination therapy with nintedanib significantly prolonged PFS, the final OS was not affected. Similar results were found in another large phase III RCT with 940 patients with advanced OVC (mostly containing HGSC, but not necessarily excluding other, more rare type of ovarian cancers), where they tested pazopanib as monotherapy [90]. Based on this, it appears that there is still a need for improvement in the treatment strategy with multi-targeted anti-angiogenic TKIs, even though some short-term results might be promising.

2.4.2. Targeting Intracellular Pathways

Most of the completed clinical trials with inhibitors targeting the intracellular signaling pathways have been early phase I trials involving combination studies of PI3K or AKT inhibitors with carboplatin-based or olaparib treatments [96][97][98][99][100] with dose determination, safety, and tolerability explored as primary outcomes. Several studies involving mTOR inhibitors have progressed to phase II [85][101][102][103][104], and most commonly these trials reported the tolerability and safety of the combinational treatments, but the efficacy appeared to be moderate. These efforts suggest that perhaps mTOR inhibitors could show more promising efficiency in ovarian cancer patients whose tumors have alterations in the PI3K-mTOR pathway, and especially when combined with anti-angiogenic agents or chemotherapeutic treatments.
For the inhibition of MAPK signaling, the MEK1-2 inhibitor binimetinib has shown encouraging results in LGSC [105], and in a small phase I study of 34 patients with platinum-resistant ovarian cancer, the clinical benefit of binimetinib was achieved in a subgroup of patients harboring alterations in the MAPK pathway [106]. Ralimetinib in combination with gemcitabine and carboplatin led to the modest improvement of progression-free survival versus chemotherapy alone; however, assessment of any molecular profiling is lacked, e.g., aberrations in MAPK-signaling pathway or BRCA status of the tumors. In light of these outcomes, MAPK inhibition in ovarian cancer warrants further exploration of its role in oncogenesis and resistance to treatment, along with strong rationales to invest in the development of potent inhibitors.
In targeting the cell cycle machinery, adavosertib used in combination with carboplatin and paclitaxel improved first-line chemotherapy in terms of progression-free survival and was relatively well-tolerated [81]. As compared to such promising results in Wee1 targeting, inhibition of ATR, a kinase-regulating CHK1/Wee1 axis and phosphorylating multiple proteins, including RAD51, by a selective agent ceralasertib was investigated in the phase II trial in combination with olaparib, resulting in excellent tolerability but with no objective response in HGSC patients [107]. Polo-like kinase PLK1, which is known to be involved in triggering chromosome segregation and in cytokinesis in general [108], was targeted by the experimental inhibitor volasertib, and the effect was evaluated in a cohort of platinum-resistant ovarian cancer patients, where it demonstrated antitumor activity, along with the manageable side effects [109].
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References

  1. Tomao, F.; D’Incalci, M.; Biagioli, E.; Peccatori, F.A.; Colombo, N. Restoring platinum sensitivity in recurrent ovarian cancer by extending the platinum-free interval: Myth or reality? Cancer 2017, 123, 3450–3459.
  2. Loret, N.; Denys, H.; Tummers, P.; Berx, G. The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance. Cancers 2019, 11, 838.
  3. Kenny, H.A.; Nieman, K.M.; Mitra, A.K.; Lengyel, E. The first line of intra-abdominal metastatic attack: Breaching the mesothelial cell layer. Cancer Discov. 2011, 1, 100–102.
  4. Bhatla, N.; Jones, A. The World Ovarian Cancer Coalition Atlas. 2018, 1, 1–39. Available online: https://worldovariancancercoalition.org/wp-content/uploads/2018/10/THE-WORLD-OVARIAN-CANCER-COALITION-ATLAS-2018.pdf (accessed on 3 October 2022).
  5. Wiltshaw, E.; Kroner, T. Phase II study of cis-dichlorodiammineplatinum(II) (NSC-119875) in advanced adenocarcinoma of the ovary. Cancer Treat. Rep. 1976, 60, 55–60.
  6. Piccart, M.J.; Bertelsen, K.; James, K.; Cassidy, J.; Mangioni, C.; Simonsen, E.; Stuart, G.; Kaye, S.; Vergote, I.; Blom, R.; et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J. Natl. Cancer Inst. 2000, 92, 699–708.
  7. Muggia, F.M.; Braly, P.S.; Brady, M.F.; Sutton, G.; Niemann, T.H.; Lentz, S.L.; Alvarez, R.D.; Kucera, P.R.; Small, J.M. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: A gynecologic oncology group study. J. Clin. Oncol. 2000, 18, 106–115.
  8. Mahmood, R.D.; Morgan, R.D.; Edmondson, R.J.; Clamp, A.R.; Jayson, G.C. First-Line Management of Advanced High-Grade Serous Ovarian Cancer. Curr. Oncol. Rep. 2020, 22, 64.
  9. Baert, T.; Ferrero, A.; Sehouli, J.; O’Donnell, D.M.; Gonzalez-Martin, A.; Joly, F.; van der Velden, J.; Blecharz, P.; Tan, D.S.P.; Querleu, D.; et al. The systemic treatment of recurrent ovarian cancer revisited. Ann. Oncol. 2021, 32, 710–725.
  10. Liu, J.F.; Barry, W.T.; Birrer, M.; Lee, J.M.; Buckanovich, R.J.; Fleming, G.F.; Rimel, B.; Buss, M.K.; Nattam, S.; Hurteau, J.; et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: A randomised phase 2 study. Lancet Oncol. 2014, 15, 1207–1214.
  11. Alvarez Secord, A.; O’Malley, D.M.; Sood, A.K.; Westin, S.N.; Liu, J.F. Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review. Gynecol. Oncol. 2021, 162, 482–495.
  12. Pagliarini, R.; Shao, W.; Sellers, W.R. Oncogene addiction: Pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Rep. 2015, 16, 280–296.
  13. Ahmed, A.A.; Etemadmoghadam, D.; Temple, J.; Lynch, A.G.; Riad, M.; Sharma, R.; Stewart, C.; Fereday, S.; Caldas, C.; Defazio, A.; et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J. Pathol. 2010, 221, 49–56.
  14. Hu, J.; Cao, J.; Topatana, W.; Juengpanich, S.; Li, S.; Zhang, B.; Shen, J.; Cai, L.; Cai, X.; Chen, M. Targeting mutant p53 for cancer therapy: Direct and indirect strategies. J. Hematol. Oncol. 2021, 14, 157.
  15. Chardin, L.; Leary, A. Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1. Front. Oncol. 2021, 11, 795547.
  16. Palaia, I.; Tomao, F.; Sassu, C.M.; Musacchio, L.; Benedetti Panici, P. Immunotherapy For Ovarian Cancer: Recent Advances And Combination Therapeutic Approaches. OncoTargets Ther. 2020, 13, 6109–6129.
  17. Cohen, P.; Cross, D.; Janne, P.A. Kinase drug discovery 20 years after imatinib: Progress and future directions. Nat. Rev. Drug Discov. 2021, 20, 551–569.
  18. Lemmon, M.A.; Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 2010, 141, 1117–1134.
  19. Yap, T.A.; Carden, C.P.; Kaye, S.B. Beyond chemotherapy: Targeted therapies in ovarian cancer. Nat. Rev. Cancer 2009, 9, 167–181.
  20. Kohler, M.; Janz, I.; Wintzer, H.O.; Wagner, E.; Bauknecht, T. The expression of EGF receptors, EGF-like factors and c-myc in ovarian and cervical carcinomas and their potential clinical significance. Anticancer Res. 1989, 9, 1537–1547.
  21. Kohler, M.; Bauknecht, T.; Grimm, M.; Birmelin, G.; Kommoss, F.; Wagner, E. Epidermal growth factor receptor and transforming growth factor alpha expression in human ovarian carcinomas. Eur. J. Cancer 1992, 28A, 1432–1437.
  22. Bonello, M.; Sims, A.H.; Langdon, S.P. Human epidermal growth factor receptor targeted inhibitors for the treatment of ovarian cancer. Cancer Biol. Med. 2018, 15, 375–388.
  23. Sheng, Q.; Liu, J. The therapeutic potential of targeting the EGFR family in epithelial ovarian cancer. Br. J. Cancer 2011, 104, 1241–1245.
  24. Chelariu-Raicu, A.; Levenback, C.F.; Slomovitz, B.M.; Wolf, J.; Bodurka, D.C.; Kavanagh, J.J.; Morrison, C.; Gershenson, D.M.; Coleman, R.L. Phase Ib/II study of weekly topotecan and daily gefitinib in patients with platinum resistant ovarian, peritoneal, or fallopian tube cancer. Int. J. Gynecol. Cancer 2020, 30, 1768–1774.
  25. Tuefferd, M.; Couturier, J.; Penault-Llorca, F.; Vincent-Salomon, A.; Broet, P.; Guastalla, J.P.; Allouache, D.; Combe, M.; Weber, B.; Pujade-Lauraine, E.; et al. HER2 status in ovarian carcinomas: A multicenter GINECO study of 320 patients. PLoS ONE 2007, 2, e1138.
  26. Oikkonen, J.; Zhang, K.; Salminen, L.; Schulman, I.; Lavikka, K.; Andersson, N.; Ojanpera, E.; Hietanen, S.; Grenman, S.; Lehtonen, R.; et al. Prospective Longitudinal ctDNA Workflow Reveals Clinically Actionable Alterations in Ovarian Cancer. JCO Precis. Oncol. 2019, 3, 1–12.
  27. Wilken, J.A.; Badri, T.; Cross, S.; Raji, R.; Santin, A.D.; Schwartz, P.; Branscum, A.J.; Baron, A.T.; Sakhitab, A.I.; Maihle, N.J. EGFR/HER-targeted therapeutics in ovarian cancer. Future Med. Chem. 2012, 4, 447–469.
  28. Davies, S.; Holmes, A.; Lomo, L.; Steinkamp, M.P.; Kang, H.; Muller, C.Y.; Wilson, B.S. High incidence of ErbB3, ErbB4, and MET expression in ovarian cancer. Int. J. Gynecol. Pathol. 2014, 33, 402–410.
  29. Saglam, O.; Xiong, Y.; Marchion, D.C.; Strosberg, C.; Wenham, R.M.; Johnson, J.J.; Saeed-Vafa, D.; Cubitt, C.; Hakam, A.; Magliocco, A.M. ERBB4 Expression in Ovarian Serous Carcinoma Resistant to Platinum-Based Therapy. Cancer Control 2017, 24, 89–95.
  30. Herr, D.; Sallmann, A.; Bekes, I.; Konrad, R.; Holzheu, I.; Kreienberg, R.; Wulff, C. VEGF induces ascites in ovarian cancer patients via increasing peritoneal permeability by downregulation of Claudin 5. Gynecol. Oncol. 2012, 127, 210–216.
  31. Burger, R.A.; Brady, M.F.; Bookman, M.A.; Fleming, G.F.; Monk, B.J.; Huang, H.; Mannel, R.S.; Homesley, H.D.; Fowler, J.; Greer, B.E.; et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N. Engl. J. Med. 2011, 365, 2473–2483.
  32. Perren, T.J.; Swart, A.M.; Pfisterer, J.; Ledermann, J.A.; Pujade-Lauraine, E.; Kristensen, G.; Carey, M.S.; Beale, P.; Cervantes, A.; Kurzeder, C.; et al. A phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med. 2011, 365, 2484–2496.
  33. Jin, M.; Cai, J.; Wang, X.; Zhang, T.; Zhao, Y. Successful maintenance therapy with apatinib inplatinum-resistant advanced ovarian cancer and literature review. Cancer Biol. Ther. 2018, 19, 1088–1092.
  34. Orbegoso, C.; Marquina, G.; George, A.; Banerjee, S. The role of Cediranib in ovarian cancer. Expert Opin. Pharmacother. 2017, 18, 1637–1648.
  35. Coleman, R.L.; Broaddus, R.R.; Bodurka, D.C.; Wolf, J.K.; Burke, T.W.; Kavanagh, J.J.; Levenback, C.F.; Gershenson, D.M. Phase II trial of imatinib mesylate in patients with recurrent platinum- and taxane-resistant epithelial ovarian and primary peritoneal cancers. Gynecol. Oncol. 2006, 101, 126–131.
  36. Schilder, R.J.; Sill, M.W.; Lee, R.B.; Shaw, T.J.; Senterman, M.K.; Klein-Szanto, A.J.; Miner, Z.; Vanderhyden, B.C. Phase II evaluation of imatinib mesylate in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group Study. J. Clin. Oncol. 2008, 26, 3418–3425.
  37. Matei, D.; Emerson, R.E.; Schilder, J.; Menning, N.; Baldridge, L.A.; Johnson, C.S.; Breen, T.; McClean, J.; Stephens, D.; Whalen, C.; et al. Imatinib mesylate in combination with docetaxel for the treatment of patients with advanced, platinum-resistant ovarian cancer and primary peritoneal carcinomatosis: A Hoosier Oncology Group trial. Cancer 2008, 113, 723–732.
  38. Posadas, E.M.; Kwitkowski, V.; Kotz, H.L.; Espina, V.; Minasian, L.; Tchabo, N.; Premkumar, A.; Hussain, M.M.; Chang, R.; Steinberg, S.M.; et al. A prospective analysis of imatinib-induced c-KIT modulation in ovarian cancer: A phase II clinical study with proteomic profiling. Cancer 2007, 110, 309–317.
  39. Helsten, T.; Elkin, S.; Arthur, E.; Tomson, B.N.; Carter, J.; Kurzrock, R. The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing. Clin. Cancer Res. 2016, 22, 259–267.
  40. Steele, I.A.; Edmondson, R.J.; Bulmer, J.N.; Bolger, B.S.; Leung, H.Y.; Davies, B.R. Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer. Oncogene 2001, 20, 5878–5887.
  41. Byron, S.A.; Gartside, M.G.; Wellens, C.L.; Goodfellow, P.J.; Birrer, M.J.; Campbell, I.G.; Pollock, P.M. FGFR2 mutations are rare across histologic subtypes of ovarian cancer. Gynecol. Oncol. 2010, 117, 125–129.
  42. Oosterhuis, G.J.; Vermes, I.; Lambalk, C.B.; Michgelsen, H.W.; Schoemaker, J. Insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in fluid from human stimulated follicles. Hum. Reprod. 1998, 13, 285–289.
  43. Yee, D.; Morales, F.R.; Hamilton, T.C.; Von Hoff, D.D. Expression of insulin-like growth factor I, its binding proteins, and its receptor in ovarian cancer. Cancer Res. 1991, 51, 5107–5112.
  44. Resnicoff, M.; Ambrose, D.; Coppola, D.; Rubin, R. Insulin-like growth factor-1 and its receptor mediate the autocrine proliferation of human ovarian carcinoma cell lines. Lab. Investig. 1993, 69, 756–760.
  45. Pejovic, T.; Pande, N.T.; Mori, M.; Mhawech-Fauceglia, P.; Harrington, C.; Mongoue-Tchokote, S.; Dim, D.; Andrews, C.; Beck, A.; Tarumi, Y.; et al. Expression profiling of the ovarian surface kinome reveals candidate genes for early neoplastic changes. Transl. Oncol. 2009, 2, 341–349.
  46. Tap, W.D.; Demetri, G.; Barnette, P.; Desai, J.; Kavan, P.; Tozer, R.; Benedetto, P.W.; Friberg, G.; Deng, H.; McCaffery, I.; et al. Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J. Clin. Oncol. 2012, 30, 1849–1856.
  47. Hubbard, R.D.; Wilsbacher, J.L. Advances towards the development of ATP-competitive small-molecule inhibitors of the insulin-like growth factor receptor (IGF-IR). Chem. Med. Chem. 2007, 2, 41–46.
  48. Liefers-Visser, J.A.L.; Meijering, R.A.M.; Reyners, A.K.L.; van der Zee, A.G.J.; de Jong, S. IGF system targeted therapy: Therapeutic opportunities for ovarian cancer. Cancer Treat. Rev. 2017, 60, 90–99.
  49. McCubrey, J.A.; Steelman, L.S.; Chappell, W.H.; Abrams, S.L.; Montalto, G.; Cervello, M.; Nicoletti, F.; Fagone, P.; Malaponte, G.; Mazzarino, M.C.; et al. Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response. Oncotarget 2012, 3, 954–987.
  50. Janku, F.; Yap, T.A.; Meric-Bernstam, F. Targeting the PI3K pathway in cancer: Are we making headway? Nat. Rev. Clin. Oncol. 2018, 15, 273–291.
  51. Levine, D.A.; Bogomolniy, F.; Yee, C.J.; Lash, A.; Barakat, R.R.; Borgen, P.I.; Boyd, J. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin. Cancer Res. 2005, 11, 2875–2878.
  52. Campbell, I.G.; Russell, S.E.; Choong, D.Y.; Montgomery, K.G.; Ciavarella, M.L.; Hooi, C.S.; Cristiano, B.E.; Pearson, R.B.; Phillips, W.A. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004, 64, 7678–7681.
  53. Matulonis, U.A.; Hirsch, M.; Palescandolo, E.; Kim, E.; Liu, J.; van Hummelen, P.; MacConaill, L.; Drapkin, R.; Hahn, W.C. High throughput interrogation of somatic mutations in high grade serous cancer of the ovary. PLoS ONE 2011, 6, e24433.
  54. Shayesteh, L.; Lu, Y.; Kuo, W.L.; Baldocchi, R.; Godfrey, T.; Collins, C.; Pinkel, D.; Powell, B.; Mills, G.B.; Gray, J.W. PIK3CA is implicated as an oncogene in ovarian cancer. Nat. Genet. 1999, 21, 99–102.
  55. Dolly, S.O.; Wagner, A.J.; Bendell, J.C.; Kindler, H.L.; Krug, L.M.; Seiwert, T.Y.; Zauderer, M.G.; Lolkema, M.P.; Apt, D.; Yeh, R.F.; et al. Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors. Clin. Cancer Res. 2016, 22, 2874–2884.
  56. Wicki, A.; Brown, N.; Xyrafas, A.; Bize, V.; Hawle, H.; Berardi, S.; Cmiljanovic, N.; Cmiljanovic, V.; Stumm, M.; Dimitrijevic, S.; et al. First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13). Eur. J. Cancer 2018, 96, 6–16.
  57. Mahadevan, D.; Chiorean, E.G.; Harris, W.B.; Von Hoff, D.D.; Stejskal-Barnett, A.; Qi, W.; Anthony, S.P.; Younger, A.E.; Rensvold, D.M.; Cordova, F.; et al. Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eur. J. Cancer 2012, 48, 3319–3327.
  58. Markman, B.; Tabernero, J.; Krop, I.; Shapiro, G.I.; Siu, L.; Chen, L.C.; Mita, M.; Melendez Cuero, M.; Stutvoet, S.; Birle, D.; et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann. Oncol. 2012, 23, 2399–2408.
  59. Shapiro, G.I.; Bell-McGuinn, K.M.; Molina, J.R.; Bendell, J.; Spicer, J.; Kwak, E.L.; Pandya, S.S.; Millham, R.; Borzillo, G.; Pierce, K.J.; et al. First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer. Clin. Cancer Res. 2015, 21, 1888–1895.
  60. Wu, P.K.; Becker, A.; Park, J.I. Growth Inhibitory Signaling of the Raf/MEK/ERK Pathway. Int. J. Mol. Sci. 2020, 21, 5436.
  61. Spaans, V.M.; Trietsch, M.D.; Crobach, S.; Stelloo, E.; Kremer, D.; Osse, E.M.; Haar, N.T.; van Eijk, R.; Muller, S.; van Wezel, T.; et al. Designing a high-throughput somatic mutation profiling panel specifically for gynaecological cancers. PLoS ONE 2014, 9, e93451.
  62. Janku, F.; Lee, J.J.; Tsimberidou, A.M.; Hong, D.S.; Naing, A.; Falchook, G.S.; Fu, S.; Luthra, R.; Garrido-Laguna, I.; Kurzrock, R. PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers. PLoS ONE 2011, 6, e22769.
  63. Holderfield, M.; Deuker, M.M.; McCormick, F.; McMahon, M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat. Rev. Cancer 2014, 14, 455–467.
  64. Cancer Genome Atlas Research, N. Integrated genomic analyses of ovarian carcinoma. Nature 2011, 474, 609–615.
  65. Champer, M.; Miller, D.; Kuo, D.Y. Response to trametinib in recurrent low-grade serous ovarian cancer with NRAS mutation: A case report. Gynecol. Oncol. Rep. 2019, 28, 26–28.
  66. Farley, J.; Brady, W.E.; Vathipadiekal, V.; Lankes, H.A.; Coleman, R.; Morgan, M.A.; Mannel, R.; Yamada, S.D.; Mutch, D.; Rodgers, W.H.; et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: An open-label, single-arm, phase 2 study. Lancet Oncol. 2013, 14, 134–140.
  67. Liu, S.; Zou, Q.; Chen, J.P.; Yao, X.; Guan, P.; Liang, W.; Deng, P.; Lai, X.; Yin, J.; Chen, J.; et al. Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer. J. Clin. Investig. 2021, 131.
  68. Campbell, R.M.; Anderson, B.D.; Brooks, N.A.; Brooks, H.B.; Chan, E.M.; De Dios, A.; Gilmour, R.; Graff, J.R.; Jambrina, E.; Mader, M.; et al. Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity. Mol. Cancer Ther. 2014, 13, 364–374.
  69. Ishitsuka, K.; Hideshima, T.; Neri, P.; Vallet, S.; Shiraishi, N.; Okawa, Y.; Shen, Z.; Raje, N.; Kiziltepe, T.; Ocio, E.M.; et al. p38 mitogen-activated protein kinase inhibitor LY2228820 enhances bortezomib-induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications. Br. J. Haematol. 2008, 141, 598–606.
  70. Aesoy, R.; Sanchez, B.C.; Norum, J.H.; Lewensohn, R.; Viktorsson, K.; Linderholm, B. An autocrine VEGF/VEGFR2 and p38 signaling loop confers resistance to 4-hydroxytamoxifen in MCF-7 breast cancer cells. Mol. Cancer Res. 2008, 6, 1630–1638.
  71. Patnaik, A.; Haluska, P.; Tolcher, A.W.; Erlichman, C.; Papadopoulos, K.P.; Lensing, J.L.; Beeram, M.; Molina, J.R.; Rasco, D.W.; Arcos, R.R.; et al. A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer. Clin. Cancer Res. 2016, 22, 1095–1102.
  72. Vergote, I.; Heitz, F.; Buderath, P.; Powell, M.; Sehouli, J.; Lee, C.M.; Hamilton, A.; Fiorica, J.; Moore, K.N.; Teneriello, M.; et al. A randomized, double-blind, placebo-controlled phase 1b/2 study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with recurrent platinum-sensitive ovarian cancer. Gynecol. Oncol. 2020, 156, 23–31.
  73. Lin, Z.P.; Zhu, Y.L.; Ratner, E.S. Targeting Cyclin-Dependent Kinases for Treatment of Gynecologic Cancers. Front. Oncol. 2018, 8, 303.
  74. Patch, A.M.; Christie, E.L.; Etemadmoghadam, D.; Garsed, D.W.; George, J.; Fereday, S.; Nones, K.; Cowin, P.; Alsop, K.; Bailey, P.J.; et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 2015, 521, 489–494.
  75. Dall’Acqua, A.; Bartoletti, M.; Masoudi-Khoram, N.; Sorio, R.; Puglisi, F.; Belletti, B.; Baldassarre, G. Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives. Cancers 2021, 13, 3035.
  76. Konstantinopoulos, P.A.; Ceccaldi, R.; Shapiro, G.I.; D’Andrea, A.D. Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer. Cancer Discov. 2015, 5, 1137–1154.
  77. Sausville, E.; Lorusso, P.; Carducci, M.; Carter, J.; Quinn, M.F.; Malburg, L.; Azad, N.; Cosgrove, D.; Knight, R.; Barker, P.; et al. Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors. Cancer Chemother. Pharmacol. 2014, 73, 539–549.
  78. Daud, A.I.; Ashworth, M.T.; Strosberg, J.; Goldman, J.W.; Mendelson, D.; Springett, G.; Venook, A.P.; Loechner, S.; Rosen, L.S.; Shanahan, F.; et al. Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors. J. Clin. Oncol. 2015, 33, 1060–1066.
  79. Slipicevic, A.; Holth, A.; Hellesylt, E.; Trope, C.G.; Davidson, B.; Florenes, V.A. Wee1 is a novel independent prognostic marker of poor survival in post-chemotherapy ovarian carcinoma effusions. Gynecol. Oncol. 2014, 135, 118–124.
  80. Lheureux, S.; Cristea, M.C.; Bruce, J.P.; Garg, S.; Cabanero, M.; Mantia-Smaldone, G.; Olawaiye, A.B.; Ellard, S.L.; Weberpals, J.I.; Wahner Hendrickson, A.E.; et al. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: A double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2021, 397, 281–292.
  81. Oza, A.M.; Estevez-Diz, M.; Grischke, E.M.; Hall, M.; Marme, F.; Provencher, D.; Uyar, D.; Weberpals, J.I.; Wenham, R.M.; Laing, N.; et al. A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer. Clin. Cancer Res. 2020, 26, 4767–4776.
  82. Wang, T.; Tang, J.; Yang, H.; Yin, R.; Zhang, J.; Zhou, Q.; Liu, Z.; Cao, L.; Li, L.; Huang, Y.; et al. Effect of Apatinib Plus Pegylated Liposomal Doxorubicin vs. Pegylated Liposomal Doxorubicin Alone on Platinum-Resistant Recurrent Ovarian Cancer: The APPROVE Randomized Clinical Trial. JAMA Oncol. 2022, 8, 1169–1176.
  83. Kim, J.W.; Mahner, S.; Wu, L.Y.; Shoji, T.; Kim, B.G.; Zhu, J.Q.; Takano, T.; Park, S.Y.; Kong, B.H.; Wu, Q.; et al. Pazopanib Maintenance Therapy in East Asian Women With Advanced Epithelial Ovarian Cancer: Results From AGO-OVAR16 and an East Asian Study. Int. J. Gynecol. Cancer 2018, 28, 2–10.
  84. Matulonis, U.A.; Sill, M.W.; Makker, V.; Mutch, D.G.; Carlson, J.W.; Darus, C.J.; Mannel, R.S.; Bender, D.P.; Crane, E.K.; Aghajanian, C. A randomized phase II study of cabozantinib versus weekly paclitaxel in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study. Gynecol. Oncol. 2019, 152, 548–553.
  85. Tew, W.P.; Sill, M.W.; Walker, J.L.; Secord, A.A.; Bonebrake, A.J.; Schilder, J.M.; Stuckey, A.; Rice, L.; Tewari, K.S.; Aghajanian, C.A. Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma: An NRG oncology/gynecologic oncology group study. Gynecol. Oncol. 2018, 151, 257–263.
  86. Hall, M.R.; Dehbi, H.M.; Banerjee, S.; Lord, R.; Clamp, A.; Ledermann, J.A.; Nicum, S.; Lilleywhite, R.; Bowen, R.; Michael, A.; et al. A phase II randomised, placebo-controlled trial of low dose (metronomic) cyclophosphamide and nintedanib (BIBF1120) in advanced ovarian, fallopian tube or primary peritoneal cancer. Gynecol. Oncol. 2020, 159, 692–698.
  87. Ray-Coquard, I.; Cibula, D.; Mirza, M.R.; Reuss, A.; Ricci, C.; Colombo, N.; Koch, H.; Goffin, F.; Gonzalez-Martin, A.; Ottevanger, P.B.; et al. Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer. Int. J. Cancer 2020, 146, 439–448.
  88. du Bois, A.; Kristensen, G.; Ray-Coquard, I.; Reuss, A.; Pignata, S.; Colombo, N.; Denison, U.; Vergote, I.; Del Campo, J.M.; Ottevanger, P.; et al. Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2016, 17, 78–89.
  89. Xia, L.; Peng, J.; Lou, G.; Pan, M.; Zhou, Q.; Hu, W.; Shi, H.; Wang, L.; Gao, Y.; Zhu, J.; et al. Antitumor activity and safety of camrelizumab plus famitinib in patients with platinum-resistant recurrent ovarian cancer: Results from an open-label, multicenter phase 2 basket study. J. Immunother. Cancer 2022, 10, e003831.
  90. Vergote, I.; du Bois, A.; Floquet, A.; Rau, J.; Kim, J.W.; Del Campo, J.M.; Friedlander, M.; Pignata, S.; Fujiwara, K.; Colombo, N.; et al. Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer. Gynecol. Oncol. 2019, 155, 186–191.
  91. Richardson, D.L.; Sill, M.W.; Coleman, R.L.; Sood, A.K.; Pearl, M.L.; Kehoe, S.M.; Carney, M.E.; Hanjani, P.; Van Le, L.; Zhou, X.C.; et al. Paclitaxel With and Without Pazopanib for Persistent or Recurrent Ovarian Cancer: A Randomized Clinical Trial. JAMA Oncol. 2018, 4, 196–202.
  92. Lee, J.M.; Annunziata, C.M.; Hays, J.L.; Cao, L.; Choyke, P.; Yu, M.; An, D.; Turkbey, I.B.; Minasian, L.M.; Steinberg, S.M.; et al. Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment. Gynecol. Oncol. 2020, 159, 88–94.
  93. Vergote, I.B.; Smith, D.C.; Berger, R.; Kurzrock, R.; Vogelzang, N.J.; Sella, A.; Wheler, J.; Lee, Y.; Foster, P.G.; Weitzman, R.; et al. A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma. Eur. J. Cancer 2017, 83, 229–236.
  94. Backes, F.J.; Wei, L.; Chen, M.; Hill, K.; Dzwigalski, K.; Poi, M.; Phelps, M.; Salani, R.; Copeland, L.J.; Fowler, J.M.; et al. Phase I evaluation of lenvatinib and weekly paclitaxel in patients with recurrent endometrial, ovarian, fallopian tube, or primary peritoneal Cancer. Gynecol. Oncol. 2021, 162, 619–625.
  95. Chan, J.K.; Brady, W.; Monk, B.J.; Brown, J.; Shahin, M.S.; Rose, P.G.; Kim, J.H.; Secord, A.A.; Walker, J.L.; Gershenson, D.M. A phase II evaluation of sunitinib in the treatment of persistent or recurrent clear cell ovarian carcinoma: An NRG Oncology/Gynecologic Oncology Group Study (GOG-254). Gynecol. Oncol. 2018, 150, 247–252.
  96. Westin, S.N.; Labrie, M.; Litton, J.K.; Blucher, A.; Fang, Y.; Vellano, C.P.; Marszalek, J.R.; Feng, N.; Ma, X.; Creason, A.; et al. Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer. Clin. Cancer Res. 2021, 27, 6354–6365.
  97. Blagden, S.P.; Hamilton, A.L.; Mileshkin, L.; Wong, S.; Michael, A.; Hall, M.; Goh, J.C.; Lisyanskaya, A.S.; DeSilvio, M.; Frangou, E.; et al. Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer. Clin. Cancer Res. 2019, 25, 1472–1478.
  98. Matulonis, U.A.; Wulf, G.M.; Barry, W.T.; Birrer, M.; Westin, S.N.; Farooq, S.; Bell-McGuinn, K.M.; Obermayer, E.; Whalen, C.; Spagnoletti, T.; et al. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann. Oncol. 2017, 28, 512–518.
  99. Bowles, D.W.; Ma, W.W.; Senzer, N.; Brahmer, J.R.; Adjei, A.A.; Davies, M.; Lazar, A.J.; Vo, A.; Peterson, S.; Walker, L.; et al. A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br. J. Cancer 2013, 109, 1085–1092.
  100. Konstantinopoulos, P.A.; Barry, W.T.; Birrer, M.; Westin, S.N.; Cadoo, K.A.; Shapiro, G.I.; Mayer, E.L.; O’Cearbhaill, R.E.; Coleman, R.L.; Kochupurakkal, B.; et al. Olaparib and alpha-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: A dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 2019, 20, 570–580.
  101. Farley, J.H.; Brady, W.E.; O’Malley, D.; Fujiwara, K.; Yonemori, K.; Bonebrake, A.; Secord, A.A.; Stephan, J.M.; Walker, J.L.; Nam, J.H.; et al. A phase II evaluation of temsirolimus with carboplatin and paclitaxel followed by temsirolimus consolidation in clear cell ovarian cancer: An NRG oncology trial. Gynecol. Oncol. 2022, 167, 423–428.
  102. Emons, G.; Kurzeder, C.; Schmalfeldt, B.; Neuser, P.; de Gregorio, N.; Pfisterer, J.; Park-Simon, T.W.; Mahner, S.; Schroder, W.; Luck, H.J.; et al. Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8). Gynecol. Oncol. 2016, 140, 450–456.
  103. Taylor, S.E.; Chu, T.; Elvin, J.A.; Edwards, R.P.; Zorn, K.K. Phase II study of everolimus and bevacizumab in recurrent ovarian, peritoneal, and fallopian tube cancer. Gynecol. Oncol. 2020, 156, 32–37.
  104. Behbakht, K.; Sill, M.W.; Darcy, K.M.; Rubin, S.C.; Mannel, R.S.; Waggoner, S.; Schilder, R.J.; Cai, K.Q.; Godwin, A.K.; Alpaugh, R.K. Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: A Gynecologic Oncology Group study. Gynecol. Oncol. 2011, 123, 19–26.
  105. Monk, B.J.; Grisham, R.N.; Banerjee, S.; Kalbacher, E.; Mirza, M.R.; Romero, I.; Vuylsteke, P.; Coleman, R.L.; Hilpert, F.; Oza, A.M.; et al. MILO/ENGOT-ov11: Binimetinib Versus Physician’s Choice Chemotherapy in Recurrent or Persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum. J. Clin. Oncol. 2020, 38, 3753–3762.
  106. Grisham, R.N.; Moore, K.N.; Gordon, M.S.; Harb, W.; Cody, G.; Halpenny, D.F.; Makker, V.; Aghajanian, C.A. Phase Ib Study of Binimetinib with Paclitaxel in Patients with Platinum-Resistant Ovarian Cancer: Final Results, Potential Biomarkers, and Extreme Responders. Clin. Cancer Res. 2018, 24, 5525–5533.
  107. Shah, P.D.; Wethington, S.L.; Pagan, C.; Latif, N.; Tanyi, J.; Martin, L.P.; Morgan, M.; Burger, R.A.; Haggerty, A.; Zarrin, H.; et al. Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer. Gynecol. Oncol. 2021, 163, 246–253.
  108. Otto, T.; Sicinski, P. Cell cycle proteins as promising targets in cancer therapy. Nat. Rev. Cancer 2017, 17, 93–115.
  109. Pujade-Lauraine, E.; Selle, F.; Weber, B.; Ray-Coquard, I.L.; Vergote, I.; Sufliarsky, J.; Del Campo, J.M.; Lortholary, A.; Lesoin, A.; Follana, P.; et al. Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer: A Randomized Phase II Groupe des Investigateurs Nationaux pour l’Etude des Cancers de l’Ovaire Study. J. Clin. Oncol. 2016, 34, 706–713.
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