Current status and outlook of targeted therapy for ovarian cancer
Song Kun Kong Beihua, Qilu Hospital, Shandong University (Jinan 250012)
Ovarian cancer has the worst prognosis among malignant tumors of the female reproductive system, and its standard treatment is currently tumor cytoreductive surgery and postoperative platinum-based combination chemotherapy. Surgery, as the main mode of ovarian cancer treatment, has not developed significantly in decades; chemotherapy is the most important adjuvant treatment modality for ovarian cancer, and new chemotherapeutic agents are constantly emerging. The latest chemotherapeutic agents including Yondelis, Canfosfamide and Epothilones are in phase III clinical trials and show good therapeutic prospects. Song Kun, Department of Gynecology, Qilu Hospital, Shandong University
In addition to surgery and chemotherapy, biological therapy (Biotherapy) is considered to be the ultimate way to cure ovarian cancer. With the development of molecular biology, the molecular mechanism of tumor development process has been elucidated, and more and more therapeutic targets for malignant tumors have emerged. Targeted therapeutic drugs have been introduced, which can target a protein or a molecule in cancer cells, i.e. molecularly targeted therapy, by regulating or blocking the function of these molecules. The corresponding drugs are called molecularly targeted agents. Molecularly targeted agents are also known as non-cytotoxic drugs, which have the characteristics of non-cytotoxicity and targeting, and mainly play a regulatory and stabilizing role on tumor cells without toxicity to normal cells, thus avoiding the toxic side effects of chemotherapy [1]. With the concept of “translational medicine”, many molecular targeting agents have moved from the laboratory to the clinic, and the most important development trend of ASCO annual meeting in recent years is that tumor molecular biology technology products have entered clinical research on a large scale, and the clinical research of molecular targeting agents has attracted attention, and tumor therapy is expected to enter a new milestone era. The most important development trend of ASCO annual meeting in recent years is that the molecular biology technology products of tumor are entering into clinical research.
The targets of molecularly targeted tumor therapy mainly include tumor cell surface receptors, molecules involved in processes such as angiogenesis, signal transduction, apoptosis and cell cycle regulation, as well as oncogenes and oncogenes. Molecular targeting agents are mainly divided into two categories: monoclonal antibodies and small molecule compounds. The following is a review of the latest research progress of molecular targeting agents for ovarian cancer.
I. ErbB receptor family inhibitors
The ErbB receptors associated with ovarian cancer are mainly ErbB1 (epidermal growth factor receptor, EGFR) and ErbB2 (Her2/neu), among which EGFR inhibitors are most widely used in clinical practice.
1, Gefitinib (Gefitinib, ZD1839), also known as Iressa (Eressa), is an oral epidermal growth factor receptor-tyrosine kinase (EGFR-TK) antagonist, which is a small molecule compound. Phase II clinical studies have shown that single-agent Gefitinib is 4% effective in the treatment of recurrent ovarian cancer (ROC) and 9% effective in EGFR-positive patients, with positive correlation between EGFR positivity and progression-free survival (PFS) and tolerable but limited efficacy of treatment side effects [2]. Gefitinib in combination with chemotherapy (topotecan) was reported to be 36.4% effective in platinum-resistant EGFR-positive ROC with mild side effects; Gefitinib in combination with tamoxifen was not effective in refractory and resistant ROC [3,4]. No phase III clinical studies on Gefitinib have been reported.
2, Erlotinib (Tarceva,OSI774): also belongs to an epidermal growth factor receptor-tyrosine kinase (EGFR-TK) antagonist, a small molecule compound. erlotinib single-agent treatment of EGFR-positive ROC is only 6% effective; erlotinib combined with carboplatin + paclitaxel is used as first-line treatment for satisfactory tumor patients after cytoreductive surgery, 10/19 patients achieved complete remission while none of the unsatisfactory surgery patients achieved complete remission; Vasey reported that Erlotinib + carboplatin + doxorubicin first-line chemotherapy followed by Erlotinib consolidation therapy resulted in a median PFS of 14.8 months and median OS of 37 months [5-7]. A phase III RCT is currently underway to explore the therapeutic value of Erlotinib consolidation therapy in patients with ovarian cancer (EORTC-55041 study)
3. Cetuximab (C225, Erbitux) : Cetuximab (cetuximab) is the most clinically advanced anti-EGFR human/mouse chimeric monoclonal antibody currently available and was approved for marketing by the FDA in 2004 for the treatment of EGFR-positive advanced colorectal cancer. Phase II clinical trials found that single-agent C225 was ineffective in treating ROC; the latest study reported that C225 combined with carboplatin was 34% effective in EGFR-positive patients for sensitive ROC; another phase II clinical study reported that Cetuximab combined with carboplatin + paclitaxel was used as a first-line regimen for advanced ovarian cancer, with preliminary results showing a complete remission rate of 86% [8 -10].
4. Herceptin (Herceptin, trastuzumab): a human/mouse chimeric monoclonal antibody against the HER-2/neu proto-oncogene product. approved by the FDA for the treatment of HER-2/neu overexpressed breast cancer. Its efficacy in ovarian cancer is undetermined. GOG reported the results of a phase II clinical trial with only 11.4% HER-2/neu expression in tumor specimens from 837 ROC patients, 55 positive patients treated with Herceptin single agent, and 41 patients available for efficacy evaluation. No antibodies were detected in the patients’ serum and the toxicity response was mild, but the overall response rate was only 7.3% and the median PFS was only 2 months. Given the low HER-2/neu expression in ovarian cancer patients and the suboptimal treatment outcome, Herceptin single agent is of limited clinical value for ovarian cancer treatment [11].
Other erbB family molecular targeting agents including canertibib (CI-1033), lapatinib (GW572016) and the monoclonal antibody Matuzumab (EMD7200) have not been proven to be of clinical therapeutic value for ROC in phase I/II clinical studies.
II. VEGF receptor family inhibitors
Vascular endothelial growth factor (VEGF), as an angiogenic factor, is involved in the process of ovarian cancer infiltration and metastasis as well as ascites formation, etc. Over-expression of VEGF increases the density of microvessels in cancer foci, and patients have poor prognosis. Anti-VEGF and VEGF receptor therapy is one of the breakthrough points in tumor treatment in recent years.
Bevacizumab (Bevacizumab, Avastin) is a recombinant humanized monoclonal antibody, which is the world’s first approved VEGF inhibitor, and inhibits endothelial cells by competitively binding to VEGF receptor (VEGFR) and blocking VEGF-mediated biological activity. This inhibits the mitosis of endothelial cells and reduces the formation of tumor neovascularization, thereby inhibiting tumor growth. Bevacizumab has shown promising results in the treatment of colorectal cancer, non-small cell lung cancer, breast cancer, etc. Several phase II clinical trials are underway with Bevacizumab alone or in combination with chemotherapy for the treatment of ovarian cancer (mainly ROC). The final results of these studies have not yet been published, but their mid-stage analyses suggest that Bevacizumab has clinical value in ovarian cancer [12, 13]. Two large phase III RCTs (GOG-0281, ICON-7) are currently underway to investigate the efficacy of Bevacizumab in combination with standard chemotherapy regimens for first-line chemotherapy and as subsequent consolidation chemotherapy in ovarian cancer.
2. Sorafenib (BAY 43-9006): Sorafenib (sorafenib, doxorubicin) is the first multi-targeted therapeutic agent approved for clinical use in the world, which is a small molecule compound with dual anti-tumor effects, on the one hand by inhibiting the RAF/MEK/ERK signaling pathway Sorafenib has been shown to be effective in advanced kidney cancer and hepatocellular carcinoma, but its use in ovarian cancer treatment is still being explored. Phase II clinical studies have shown that Sorafenib combined with gemcitabine as second-line therapy resulted in stable disease in 60.4% of patients, however only 4.7% achieved clinical partial remission, median PFS of 5.4 months, median OS of 13.3 months, and low incidence of serious toxic reactions [14, 15]. The efficacy of Sorafenib in combination with carboplatin + paclitaxel for ROC is currently being investigated, while the efficacy of Sorafenib in combination with other targeted agents such as Bevacizumab is also in phase II clinical studies.
VEGF-trap: VEGF-trap is a special anti-angiogenic substance that binds and inactivates VEGF and consists of a constant region of IgG fused with two different VEGFRs (VEGFR-1 and VEGFR-2). A randomized multicenter phase II clinical trial is currently underway internationally, including the participation of 62 study centers in Europe, the United States and Canada, and 162 patients have been enrolled and 45 are available for efficacy evaluation, with preliminary results showing an efficiency of 11% for single-agent VEGF-trap in the treatment of platinum-resistant ROC [16], with a low incidence of serious toxicities.VEGF-trap combined with chemotherapeutic agents for ROC is in the clinical research phase.
Other anti-angiogenic molecular targeted therapeutics include Sunitinib (SU11248), AZD6474, AZD2171, etc. SU11248 selectively acts on PDGFR/VEGFR/KIT/FLT3 and is a multi-targeted biologically targeted small molecule drug like Sorafenib; AZD6474 is a selective inhibitor of VEGFR /EGFR and AZD2171 is a selective inhibitor of VEGFR. All are currently in clinical trials to explore their efficacy against ROC.
Third, induction of apoptosis and reversal of drug-resistant agents
It is well known that chemotherapeutic drugs can induce apoptosis in tumor cells, and it is a feasible new strategy for tumor treatment to develop new targeted drugs to directly induce apoptosis or lower the threshold of apoptosis to reverse the resistance of chemotherapeutic drugs and to play a synergistic or strengthening effect with chemotherapeutic agents.
1. TLK-286: TLK-286 is a pro-drug activated by high concentration of glutamyl S-transferase (GST) in tumor cells, so its potential target is drug-resistant tumor cells mediated by high concentration of GST-π, with no cross-resistance and synergistic effect with standard chemotherapeutic agents. The drug has been shown to be effective in ovarian cancer in phase I clinical studies. Upon activation TLK-286 initiates the apoptotic process in cells. A phase II clinical trial found that 31 patients with platinum-resistant refractory ovarian cancer achieved complete remission in 1 case, partial remission in 1 case, and stable disease in 12 cases [17]. A phase III RCT study of TLK286 in the United States (ASSIST-3) is ongoing and has completed patient enrollment, and results are expected to be published in the near future.
2. P-gp inhibitors: overexpression of P-glycoprotein (P-gp) is the main cause of multidrug resistance (MDR), and P-glycoprotein inhibitors can inhibit the efflux of P-glycoprotein to tumor drugs and increase the concentration of drugs in tumor cells, thus reversing tumor MDR. The cyclophilin analogue PSC-833 is effective in inhibiting P-gp in vitro and has been used in clinical trials. A phase III RCT reporting 762 patients randomized to paclitaxel combined with carboplatin first-line chemotherapy who received either PSC-833 or placebo concurrently found no improvement in remission or survival rates. suggesting that PSC-833 is ineffective against chemotherapy resistance in ovarian cancer [18]. In contrast, another independent study utilized biricodar (biricodar, INCEL, VX-710), which reverses multidrug resistance protein (MRP1) and P-gp-mediated resistance in vitro, in combination with paclitaxel in 45 patients with paclitaxel-resistant ovarian cancer, with three cases in partial remission, 12 cases maintaining stable status, and 31% of patients achieving a 50-90% reduction in CA125 levels by 24 weeks. This study confirmed the effectiveness of biricodar in paclitaxel-resistant ovarian cancer [19].
3. Other chemotherapy resistance reversal agents
The synthetic amino acid buthionine sulfoximine (BSO) is a glutathione synthase inhibitor that reverses cisplatin resistance by inhibiting glutathione synthesis. phase I clinical trials have demonstrated that BSO depletes glutathione in tumors, resulting in remission in two cases of drug-resistant ovarian cancer.
Decitabine, which demethylates certain methylation genes such as MLH1, was found to reverse cisplatin resistance due to deletion of the DNA mismatch repair system (MMR) in in vitro and in vivo studies. A phase I clinical trial of decitabine in combination with cisplatin is currently underway, and preliminary results suggest that the case is simple and easy to administer, with tolerable toxic side effects.
HGS-ETR1 (mapatumumab), a human monoclonal antibody that specifically binds to TRAIL-receptor 1 protein, induces death of TRAIL-receptor 1-expressing cancer cells and has broad antitumor activity. Because HGS-ETR1 mimics the activity of the natural TRAIL-receptor 1 protein, it is considered an agonist antibody. phase II clinical trials have shown HGS-ETR1 to be effective against non-small cell lung cancer, advanced non-Hodgkin’s lymphoma and advanced rectal cancer. Additional efficacy in ovarian cancer has not been reported.
ZD9331 is a specific inhibitor of thymidylate synthase that, unlike other folate inhibitors, does not require polyglutamate synthase (FPGS) to function, thereby overcoming FPGS-mediated drug resistance, and is now clinically effective and less toxic in solid cancers, including ovarian cancer.
IV. PDGF and c-Kit inhibitors
Gleevec (GLEEVEC, Imatinib mesylate) is a new generation of oral small molecule targeted anticancer drug with inhibitory effect on platelet-derived growth factor (PDGF) receptor protein kinase, GLEEVEC can also inhibit two other kinases BCR-ABL and C-Kit activity in addition to PDGF activity. malignant stromal cell tumors, which has been widely used clinically with good therapeutic results. However, its efficacy in ovarian cancer has not been confirmed. The results of a phase II clinical trial by the Southwest Oncology Group (SWOG) in the United States showed that Gleevec treated platinum paclitaxel-resistant ROC with positive markers (c-Kit/PDGFR/Abl) and 33% of patients had stable disease and no patients achieved clinical remission [20]. The results of another phase II clinical trial were similar to theirs, in which 19 marker-positive ROC patients were treated with Gleevec without achieving significant clinical efficacy [21]. Based on the results of the current study, Gleevec has limited value in gynecologic oncology.
V. Gene therapy
The P53 gene is the most widely studied oncogene, and P53 gene therapy for ovarian cancer had been highly anticipated, however, although adenovirus-mediated P53 gene therapy for recurrent ovarian cancer had some efficacy in phase I/II clinical trials and was well tolerated by patients. However, in a prematurely discontinued phase III RCT study, P53 gene therapy did not improve patient survival [22, 23].
The tumor lysing virus Onyx-015 specifically infects P53 gene inactivated tumor cells and the virus replicates profusely thereby destroying tumor cells. Phase I studies have shown that Onyx-015 is safe and reliable for ROC treatment, well tolerated by patients, and is a promising gene therapy modality [24].
VI. Other targeting agents
1. CA125-targeting antibody: oregovomab (OvaRex) is a monoclonal antibody targeting CA125 that binds specifically to CA125, which is highly expressed in ovarian cancer cells, to improve the body’s ability to recognize ovarian cancer cells and has a specific killing effect. Patients were randomized to receive either OvaRex consolidation therapy or placebo-only control, and the results of a 5-year follow-up found that OS was prolonged by nearly 10 months after OvaRex treatment (57.5 vs. 48.6 months), with 5-year survival rates of 47% and 37%, respectively, and two phase III RCTs are currently underway to further determine its therapeutic value in ovarian cancer [25].
Seiden reported the results of a so-called SMART study (Monoclonal Antibody RadioimmunoTherapy), in which 447 ovarian cancer patients who achieved complete clinical remission after standard treatment were randomized to a single study. Patients with ovarian cancer who achieved complete clinical remission after standard treatment were randomized to receive either intraperitoneal radioimmunoconcentration with yttrium 90-labeled HMFG1 murine monoclonal antibody (R1549) or follow-up observation only, with a median follow-up of 3.5 years, with no statistical difference in PFS and OS between the two groups [26].
3. Matrix metalloproteinase inhibitors: In a phase III RCT study, the matrix metalloproteinase inhibitor BAY 12-9566 (tanomastat) was used for ovarian cancer consolidation therapy, and BAY 12-9566 did not prolong PFS (10.4 vs 9.2 months) and OS (13.9 vs 11.9 months) in patients compared with placebo controls [27].
VII. Issues and outlook
With the continuous research on the mechanism of tumorigenesis and development, targeted therapy will become a new choice for the treatment of malignant tumors. Compared with traditional chemotherapy, targeted therapy will play an increasingly important role in tumor treatment with its advantages of targeting, and is expected to become the ultimate means of curing cancer. However, summarizing the above clinical studies in ovarian cancer, no clear therapeutic advantage of molecularly targeted agents over cytotoxic drugs, either monoclonal antibodies or small molecule compounds, has been established. Treatment with molecular targeted agents alone is usually ineffective and requires combination with other therapeutic modalities such as chemotherapy to achieve certain efficacy. The development of tumor is a multi-gene and multi-stage process, and the current understanding of malignant tumors is far from adequate. Single-factor and single-target drug development strategies can hardly meet the needs of preventing and treating malignant tumors; the heterogeneity of tumors and individual patient polymorphism lead to individual differences in drug efficacy and toxicity. Therefore, discovering new molecular therapeutic targets for tumors, establishing standardized treatment protocols, exploring scientific treatment strategies, and developing multi-target antitumor drugs are among the issues that need to be addressed in the future, while the best mode of tumor treatment should emphasize comprehensive treatment at present. In terms of ovarian cancer, biologic therapy including molecular targeted therapy is mostly used as second- or third-line therapy or consolidation therapy, even as first-line therapy, it is also used in combination with chemotherapy, while the ultimate efficacy of biologic therapy is still to be confirmed by evidence-based medical evidence provided by the results of a large-scale phase III RCT. Until then, the standard treatment for ovarian cancer remains tumor cytoreductive surgery and postoperative platinum-based combination chemotherapy.