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Kinase Inhibitors in the Treatment of Ovarian Cancer: History
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Contributor: Aikaterini Skorda ,
Marie Lund Bay
, Sampsa Hautaniemi , Alexandra Lahtinen , Tuula Kallunki

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].

This entry is adapted from the peer-reviewed paper 10.3390/cancers14246257

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