Platinum-based Drugs Research Articles

Thermosensitive Liposomes Encapsulating Nedaplatin and Picoplatin Demonstrate Enhanced Cytotoxicity against Breast Cancer Cells

Thermosensitive liposomes (TSL) have been used for localized temperature-responsive release of chemotherapeutics into solid cancers, with a minimum of one invention currently in clinical trials (phase III). In this study, TSL was designed using a lipid blend comprising 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000] (DSPE-PEG-2000) (molar ratio of 88:9:2.8:0.2). Either nedaplatin (ND) or p-sulfonatocalix[4]arene-nedaplatin was encapsulated in the aqueous inner layer of TSL to form (ND-TSL) or p-SC4-ND-TSL, respectively. The hydrophobic platinum-based drug picoplatin (P) was loaded into the external lipid bilayer of the TSL to develop P-TSL. The three nanosystems were studied in terms of size, PDI, surface charge, and on-shelf stability. Moreover, the entrapment efficiency (EE%) and release % at 37 and 40 °C were evaluated. In a 30 min in vitro release study, the maximum release of ND, p-SC4-ND, and picoplatin at 40 °C reached 74, 79, and 75%, respectively, compared to approximately 10% at 37 °C. This demonstrated temperature-triggered drug release from the TSL in all three developed systems. The designed TSL exhibited significant in vitro anticancer activity at 40 °C when tested on human mammary gland/breast adenocarcinoma cells (MDA-MB-231). The cytotoxicity of ND-TSL, p-SC4-ND-TSL, and P-TSL at 40 °C was approximately twice those observed at 37 °C. This study suggests that TSL is a promising nanoplatform for the temperature-triggered release of platinum-based drugs into cancer cells.

Activation imaging: New concept of visualizing drug distribution with wide-band X-ray and gamma-ray imager

The visualization of drug distribution in the body plays an essential role in cancer therapy. Although various imaging methods have been proposed, a versatile method for visualizing multiple types of drugs is yet to be established. Therefore, we propose “activation imaging” as a new method for visualizing various drugs. Activation imaging activates drugs with protons or neutrons, enabling the visualization of drugs using gamma rays and/or X-rays emitted from the activated drugs. This method does not require labeling drugs with specific tracers because the constituent elements of the drugs become radiotracers through proton/neutron irradiation. Therefore, activation imaging can be used to visualize various types of existing drugs, including anticancer drugs, drug carriers, and contrast agents. In this study, we activated drugs using low-energy neutrons and performed gamma-ray spectroscopy and imaging. We used several types of drugs, such as cisplatin, a platinum-based anticancer drug; gold and platinum nanoparticles, which are promising drug carriers; and gadoteridol, a gadolinium-based contrast agent. Imaging was performed using a hybrid Compton camera, which can visualize X-rays and gamma rays ranging from a few tens of keV to nearly 1 MeV. With this wide-band X-ray and gamma-ray imager, various X-rays and gamma rays emitted from drugs can be visualized. Moreover, high-performance liquid chromatography (HPLC) was performed for cisplatin and gadoteridol to investigate whether the molecules of the drugs were degraded by neutron irradiation. Consequently, gamma rays from the activated drugs were observed in the spectra, and all drugs were successfully visualized. Furthermore, the HPLC results showed that most gadoteridol and cisplatin molecules retained their structure through activation.

240 (PB-064) Poster - A novel biomarker to predict DNA-Repair-inhibitor response in stage I-III high risk breast cancer patients

Background: The combinations of PARP inhibitor (PARPi) and platinum-based drugs are gaining more interest as first line therapy for early-stage breast cancer. The I-SPY2 trial (NCT01042379) qualified different DNA-Damage-Repair (DDR) deficiency biomarkers that predict response to DNA damage agents. Here we aimed to translate the I-SPY2 research findings to a robust clinical grade platform signature to predict sensitivity to PARPi and platinum-based chemotherapy.

Tumor-Infiltrating Lymphocytes (TILs) in Epithelial Ovarian Cancer: Heterogeneity, Prognostic Impact, and Relationship with Immune Checkpoints.

Epithelial ovarian cancers (EOC) are often diagnosed at an advanced stage with carcinomatosis and a poor prognosis. First-line treatment is based on a chemotherapy regimen combining a platinum-based drug and a taxane-based drug along with surgery. More than half of the patients will have concern about a recurrence. To improve the outcomes, new therapeutics are needed, and diverse strategies, such as immunotherapy, are currently being tested in EOC. To better understand the global immune contexture in EOC, several studies have been performed to decipher the landscape of tumor-infiltrating lymphocytes (TILs). CD8+ TILs are usually considered effective antitumor immune effectors that immune checkpoint inhibitors can potentially activate to reject tumor cells. To synthesize the knowledge of TILs in EOC, we conducted a review of studies published in MEDLINE or EMBASE in the last 10 years according to the PRISMA guidelines. The description and role of TILs in EOC prognosis are reviewed from the published data. The links between TILs, DNA repair deficiency, and ICs have been studied. Finally, this review describes the role of TILs in future immunotherapy for EOC.

Metformin Improves Ovarian Cancer Sensitivity to Paclitaxel and Platinum-Based Drugs: A Review of In Vitro Findings.

Ovarian cancer is one of the most dangerous gynecologic cancers worldwide, showing a high fatality rate and recurrence due to diagnosis at an advanced stage of the disease and the occurrence of chemoresistance, which weakens the therapeutic effects of the chemotherapeutic treatments. In fact, although paclitaxel and platinum-based drugs (carboplatin or cisplatin) are widely used alone or in combination to treat ovarian cancer, the occurrence of chemoresistance significantly reduces the effects of these drugs. Metformin is a hypoglycemic agent that is commonly used for the treatment of type 2 diabetes mellitus and non-alcoholic fatty liver disease. However, this drug also shows anti-tumor activity, reducing cancer risk and chemoresistance. This review analyzes the current literature regarding the role of metformin in ovarian cancer and investigates what is currently known about its effects in reducing paclitaxel and platinum resistance to restore sensitivity to these drugs.

Theranostic Hyaluronan Coated EDTA Modified Magnetic Mesoporous Silica Nanoparticles for Targeted Delivery of Cisplatin

One of the eminent capabilities of nanoparticles in drug delivery is active targeting. Mesoporous silica nanoparticles (MSNs) are among the well-known nanocarriers, which have been utilized for gene and drug deliveries due to their particular physical and chemical properties. The present study aimed to introduce an engineered type of EDTA-modified Magnetic Mesoporous Silica Nanoparticles (MMSNs) with hyaluronan coating as a theranostic agent for delivery of an anti-cancer drug (cisplatin). EDTA was first applied as a ligand for platinum-based drug loading. The nanoparticles were synthesized in several steps. The properties of each step were characterized by various techniques such as Fourier transform infrared (FT-IR), X-Ray diffraction (XRD), vibrating sample magnetometer (VSM), and N2 adsorption/desorption. Morphology was also checked by field emission scanning electron microscopy (FE-SEM) and Transmission electron microscopy (TEM). In addition, loading capacity (LC) and loading efficiency, and in vivo release of cisplatin were analyzed through ICP-OES. Eventually, the plasma concentration profile and cisplatin pharmacokinetics parameters after intravenous administration of EDTA-MMSN @ HA were evaluated. The average particle diameters of prepared structure were approximate range of 70–100 nm. The profile release of cisplatin in acidic medium was faster in 72 h, which confirmed the pH-responsive behavior of the nanoparticles. As the results of cytotoxicity showed, coating with HA can improve the internalization of nanoparticles in cancer cells compared to normal cells. Finally, EDTA-MMSN @ HA can be introduced as a new favor biocompatible and biodegradable nanoplatform for targeted drug delivery which can improve pharmacokinetic parameters. Overall, this study successfully synthesized a novel multifunctional pH-responsive MSN for efficient drug delivery and magnetic resonance imaging.

Stimuli-responsive platinum and ruthenium complexes for lung cancer therapy.

Lung cancer is the most common cause of cancer-related deaths worldwide. More efficient treatments are desperately needed. For decades, the success of platinum-based anticancer drugs has promoted the exploration of metal-based agents. Four ruthenium-based complexes have also entered clinical trials as candidates of anticancer metallodrugs. However, systemic toxicity, severe side effects and drug-resistance impeded their applications and efficacy. Stimuli-responsiveness of Pt- and Ru-based complexes provide a great chance to weaken the side effects and strengthen the clinical efficacy in drug design. This review provides an overview on the stimuli-responsive Pt- and Ru-based metallic anticancer drugs for lung cancer. They are categorized as endo-stimuli-responsive, exo-stimuli-responsive, and dual-stimuli-responsive prodrugs based on the nature of stimuli. We describe various representative examples of structure, response mechanism, and potential medical applications in lung cancer. In the end, we discuss the future opportunities and challenges in this field.

Overcoming therapeutic resistance to platinum-based drugs by targeting Epithelial-Mesenchymal transition.

Platinum-based drugs (PBDs), including cisplatin, carboplatin, and oxaliplatin, have been widely used in clinical practice as mainstay treatments for various types of cancer. Although there is firm evidence of notable achievements with PBDs in the management of cancers, the acquisition of resistance to these agents is still a major challenge to efforts at cure. The introduction of the epithelial-mesenchymal transition (EMT) concept, a critical process during embryonic morphogenesis and carcinoma progression, has offered a mechanistic explanation for the phenotypic switch of cancer cells upon PBD exposure. Accumulating evidence has suggested that carcinoma cells can enter a resistant state via induction of the EMT. In this review, we discussed the underlying mechanism of PBD-induced EMT and the current understanding of its role in cancer drug resistance, with emphasis on how this novel knowledge can be exploited to overcome PBD resistance via EMT-targeted compounds, especially those under clinical trials.

Nivolumab for Platinum-refractory and -sensitive Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma.

Nivolumab has antitumor efficacy in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) who relapse within 6 months after platinum-based therapy; however, the efficacy of nivolumab for platinum-sensitive R/M HNSCC has not been shown. Therefore, this study compared the efficacy and safety of nivolumab for platinum-refractory and platinum-sensitive R/M HNSCC. This was a retrospective study of patients who received nivolumab for R/M HNSCC who had been previously treated with platinum-based anticancer drugs. Patients were divided into a platinum-sensitive and a platinum-refractory group, and progression-free survival (PFS), overall survival (OS), the overall response rate (ORR) [complete response (CR) + partial response (PR)], the disease control rate (DCR) (CR + PR + stable disease), and the incidence of immune-related adverse events (irAEs) were compared between the two groups. We included 88 patients with squamous cell carcinoma: 60 with platinum-refractory disease and 28 with platinum-sensitive disease. The median PFS in the platinum-refractory and platinum-sensitive groups were 2.7 months and 5.3 months, respectively (p=0.03), and the median OS were 8.8 months and 17.1 months, respectively (p=0.06). There were no significant differences in the ORR, DCR, or incidence of irAEs between the two groups (p>0.99, p=0.11, and p>0.99, respectively). Nivolumab is a safe and effective treatment for platinum-sensitive R/M HNSCC.

The power of a novel combined anticancer therapy: challenge and opportunity of micotherapy in the treatment of Glioblastoma Multiforme

Glioblastoma (GBM) is the most common and mortal primary brain tumor in human. After standard therapies, that include surgical resection followed by radiotherapy and chemotherapy, it is difficult to completely remove the tumor and the development of relapses and resistance is almost inevitable. The chemotherapy now available also show important side effects, to overcame those limitation, new platinum-based drugs are being synthetized, Pt(IV)Ac-POA, (OC-6–44)-acetate-diamine-chloride(2-(2-propynyl)octanoato)platinum(IV), a prodrug having an Histone-3-DeAcetylase-Inhibitor as axial ligands, is one of them. Moreover, new compounds of plant origin are increasingly seen as potential sources of benefits in oncological treatments. The aim of the study is to investigate the possible contribution of micotherapy in the fight against GBM, its role in the metabolism of reactive oxygen species (ROS) and its synergic effect with a new platinum-based compound, Pt(IV)Ac-POA, on human glioblastoma U251 cells. Through cytofluorimetric and immunofluorescence analysis, the ability of the micotherapy in study to regulate the cell cycle was assessed, and its importance in controlling the cellular redox state was also revealed, opening to the possibility of a new therapy in which micotherapy can support the activity of new chemotherapy while reducing its side effects controlling inflammatory conditions in the microenvironment. Additionally, the combined therapy appeared able to induce regulated form of necrosis, such as ferroptosis, and to hinder the establishment of resistance mechanisms.

315. PATIENT-DERIVED ESOPHAGEAL ADENOCARCINOMA ORGANOIDS TREATED WITH CHEMOTHERAPEUTIC AGENTS MAY PREDICT TUMOR RESPONSE IN VIVO

Abstract The current management of locally-advanced esophageal adenocarcinoma (EAC) includes neoadjuvant therapy; however, there are no robust markers that predict treatment response. While 25% of patients will have a complete pathological response, up to 40% will have little or no response. Identification of this non-responsive subgroup prior to treatment could allow personalization of induction regimens. This study aims to determine the feasibility of using patient-derived organoids (PDOs) generated from EAC to predict induction treatment response. PDOs were generated from endoscopic biopsies taken pre-treatment in patients with locally advanced (LA) or metastatic (M) esophageal cancer. For those with LA disease, samples were also taken post-resection. PDOs were established, passaged, then treated with a drug panel of platinum-based drugs, taxane-based drugs, topoisomerase inhibitors and 5-flurouracil. Treatment response curves and growth metrics were mapped back to treatment response, based on pathological tumor regression grade in the LA group and clinical response based on cross-sectional imaging in the M group. 19 organoids from 7 LA tumors and 10 organoids from 8 M tumors were treated. For LA PDOs, there were significant correlations between cisplatin IC50 (p = 0.007), EC50 (p = 0.002) and TRG. There was a correlation between paclitaxel AUC and TRG (p = 0.02). There were no correlations with irinotecan or 5-FU drug metrics and TRG. For M PDOs, there was a correlation between cisplatin and clinical response for AUC (p = 0.04), and a trend for IC50 (p = 0.07). There were also correlations between paclitaxel and clinical response for IC50 (p = 0.04) and AUC (p = 0.01). There were no correlations with irinotecan or 5-FU. Treatment responses of EAC PDOs treated in vitro with standard chemotherapeutic agents may predict clinical response in the corresponding patient’s tumor. A PDO model may form the basis for screening therapeutic agents in the neoadjuvant window, allowing the development of truly personalized neoadjuvant strategies.

Effect of the PARP inhibitor veliparib on germ cell tumor cell lines.

Germ cell tumors (GCTs) usually represent efficiently curable neoplasms due to their chemosensitivity to platinum-based therapeutic regimen. However, some patients develop therapeutic resistance and succumb to their disease. Novel therapeutic approaches are therefore needed for these patients. It has previously been demonstrated that poly (ADP-ribose) polymerase (PARP) expression is upregulated in GCTs compared with normal testis tissue. Therefore, PARP expression was analyzed in GCT cell lines and xenografts and it was examined whether its inhibition by veliparib can reverse cisplatin-resistance. Its expression was analyzed in sensitive and cisplatin-resistant variants (referred to as CisR throughout the manuscript) GCT cell lines and xenografts using quantitative PCR, western blotting and immunohistochemistry. The present study investigated whether the combination of cisplatin with the PARP inhibitor veliparib increased the cytotoxic effect of cisplatin in vitro using a luminescent viability assay and an immunodeficient mouse model in vivo. PARP expression was observed in all tested cell lines, with the highest expression in embryonal carcinoma (EC) cell lines and xenografts. Low or no expression was detected in the JEG-3 choriocarcinoma cell line pairs and xenografts. The combination of veliparib and cisplatin or carboplatin was examined in the cisplatin-resistant NTERA-2 CisR and NCCIT CisR EC cell lines and synergistic effects were observed in NTERA-2 CisR cells. However, in vivo analysis did not confirm this synergy. The present data indicated PARP expression in GCT cell lines and xenografts. However, veliparib failed to increase the cytotoxicity of platinum-based drugs. Therefore, further research is warranted to effectively inhibit PARP using different PARP inhibitors or other drug combinations.

Precise quantitative evaluation of pharmacokinetics of cisplatin using a radio-platinum tracer in tumor-bearing mice.

ObjectiveThe platinum-based antineoplastic drug cisplatin is commonly used for chemotherapy in clinics. This work aims to demonstrate a radio-platinum tracer is useful for precisely quantifying small amounts of platinum in pharmacokinetics studies.MethodsA cisplatin radiotracer (radio-cisplatin) was synthesized, and a comprehensive evaluation of cisplatin over 7 days after its intravenous injection into nude mice bearing a subcutaneous lung tumor (H460) was conducted.ResultsA biphasic retention curve in the whole body and blood was observed [T1/2(α) = 1.14 h, T1/2(β) = 5.33 days for the whole body, and T1/2(α) = 23.9 min, T1/2(β) = 4.72 days for blood]. The blood concentration decreased within 1 day after injection. Most of the intact cisplatin was excreted via the kidneys in the early time points, and a small part was distributed in tissues including tumors. The plasma protein binding rate of cisplatin increased rapidly after injection, and the protein-bound cisplatin remained in the blood longer than intact cisplatin. The peak uptake in H460 tumors was 4.7% injected dose per gram at 15 min after injection, and the area under the curve (AUC0–7 days) was approximately one-half to one-third of the AUC0–7 days in the kidneys, liver, and bone, where some toxicity is observed in humans.ConclusionThe radio-platinum tracer revealed the highly quantitative biodistribution of cisplatin, providing insights into the properties of cisplatin, including its adverse effects. The tracer enables a precise evaluation of pharmacokinetics for platinum-based drugs with high sensitivity.

A significantly non-toxic novel Cobalt(III) Schiff base complex induces apoptosis via G2-M cell cycle arrest in human breast cancer cell line MCF-7

AimsMetal complexes have ignited considerable interest in the field of chemotherapy after the serendipitous discovery of cisplatin but the severe toxicity of these platinum-based drugs compelled researchers to search for newer, more effective lesser toxic anticancer drugs. Materials and methodsStructural analysis is done by different physicochemical techniques including X-ray single crystallography. Toxicity study has been done in normal Swiss albino mice. MTT assay assessed cell viability. Apoptosis, cell cycle arrest, and cell proliferation were assessed by FACS using Annexin V-PI, PI, and CFSE staining respectively. Western blot quantifies protein expression. While cell migration was studied by wound healing assay. Key findingsOne-pot synthesis of a novel mononuclear cobalt(III)-Schiff base complex (1) (>99 % purity) and its complete characterization have been done. Cell viability assay showed that 1 (IC50 = 16.81 ± 1.33 μM) exhibits cytotoxicity at much lower concentration in comparison to oxaliplatin (IC50 = 31.4 ± 0.69 μM) against MCF-7 cells for 24 h of therapy without being overly toxic to human PBMCs (IC50 ≥ 60 μM). Additional in vitro studies demonstrated that 1 induces apoptosis via G2-M cell cycle arrest and reduces cell proliferation as well as cell migration in MCF-7 cells. In vivo subacute toxicity (28 days) and systemic chronic toxicity (40 days) studies were carried out in normal Swiss albino mice showed 1 is significantly nontoxic to the host. SignificanceThe readily synthesizable, significantly nontoxic cobalt complex with appreciable anticancer activity implies that it might be an effective chemotherapeutic agent for new-age anti-tumor medication.

Protective effect of rosmarinic acid on the transmembrane transporter Ctr1 expression in cisplatin-treated mice.

Cisplatin (cis-diamminedichloroplatinum(II), CP) is a platinum-based anticancer drug widely used in the treatment of solid malignancies. However, its side effects, particularly nephrotoxicity, are limiting factors in its clinic use. Rosmarinic acid (RA), a natural antioxidant compound, is reported to attenuate oxidative stress and associated pathophysiological outcomes. Our study aimed to explore the protective effect of RA against CP-induced acute kidney injury (AKI). We investigated the effect of RA at the dose of 100 mg/kg on AKI induced by CP (20 mg/kg) in mice. Various parameters of nephrotoxicity such as levels of serum electrolytes, albumin, and globulin were measured using standardized methods. Besides, a specific biomarker of damage to proximal tubular cells, kidney injury molecule-1 (Kim-1), was measured in the serum by ELISA. mRNA expression of Kim-1 and a transmembrane transporter, copper transporter 1 (Ctr1), was analyzed by quantitative reverse transcriptase-polymerase chain reaction. CTR1 expression was also analyzed by western blot technique. RA treatment restored the downregulated CTR1 , a renal transmembrane transporter in CP-treated mice. It was accompanied by a reduction in the level of serum albumin and globulin. Serum electrolytes such as Na+, K+, and Ca2+ in CP-treated mice were found to be restored with RA treatment. Moreover, RA also significantly downregulated the increased expression of nephrotoxicity biomarker KIM-1. Overall, RA proved to be an effective nephroprotective compound which afforded protection at cellular and subcellular levels with an appreciable modulatory effect on a transmembrane transporter.

Reactions of Ru(III)-drugs KP1019 and KP418 with guanine, 2'-deoxyguanosine and guanosine: a DFT study.

Ruthenium (Ru)-based anticancer drugs are considered to be novel alternatives of platinum-based drugs. They exhibit potent cytotoxicity against the cancer cells and hence are useful for the treatment of cancer. Herein, the density functional theory calculations in the gas phase and aqueous media are carried out to study the reactions of two Ru(III)-based drugs such as KP1019 and KP418 with the N7 site of guanine (G), 2'-deoxyguanosine (dGua), and guanosine (Gua) to understand their reactivity against the DNA and RNA. All the reactions are found to be exothermic. The activation free energies and rate constants of these reactions indicate that KP1019 and KP418 would react with the dGua more readily than Gua. Hence, the binding of these drugs with the DNA would be more preferred as compared to RNA. It is further found that among these drugs, KP1019 would be more reactive than KP418 in agreement with the experimental observation. Thus, this study is expected to aid in the future development of potent anticancer drugs.

A clinical case of repeat use of PARP inhibitors in a patient with <i>mBRCA</i>-associated ovarian cancer

Backgraound. High-grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer. The prevalence of BRCA1/2 germline mutations is the highest in HGSOC. patients with germline BRCA gene mutations are more likely to respond to platinum-based chemotherapy. Clinical trials demonstrate the effectiveness of PARP inhibitors in the treatment of BRCA-associated ovarian cancer. Re-administration of PARP inhibitors after response to platinum-based chemotherapy demonstrates an increase in progression-free survival rates regardless of BRCA status. it is important for understanding the development of molecular mechanisms of resistance to platinum drugs and PARP inhibitors, as well as for developing new treatment strategies and tools to overcome resistance. Case description. This clinical case of BRCA-associated hereditary ovarian cancer demonstrates the efficacy and good tolerability of PARP inhibitor maintenance therapy following the treatment of the first relapse, as well as the efficacy of re-administration of PARP inhibitors following the treatment of the second relapse. The short-course of re-treatment with PARP inhibitors was accompanied by the development of multidrug resistance. the overall survival time was 112 months. Conclusion. The presence of mutations in BRCA1/2 genes is a promising justification for the administration of maintenance therapy with PARP inhibitors. Re-administration of PARP inhibitor maintenance therapy for relapsed ovarian cancer is currently being considered as a possible therapeutic option. deciphering the molecular mechanisms of resistance to PARP inhibitors is of paramount importance for the development of new treatment strategies and tools to overcome chemoresistance, re-sensitization of the tumor to platinum-based drugs or PARP inhibitors.

1241P Phase Ib study of futibatinib plus pembrolizumab in patients with advanced or metastatic solid tumors: Tolerability results and antitumor activity in esophageal carcinoma

Combination therapy using FGFR inhibitors and Immune checkpoint inhibitors (ICIs) are being explored as a novel strategy for cancer patients (pts). Here, we report the safety and tolerability of FGFR inhibitor futibatinib plus pembrolizumab in pts with advanced (adv) or metastatic solid tumors and first results for preliminary antitumor activity in pts with esophageal carcinoma (EC). This study consists of Feasibility phase (FP) and Expansion phase (EP). In FP, pts with adv or metastatic solid tumors harboring FGF/FGFR abnormalities received futibatinib 20 mg once daily (QD) plus pembrolizumab 200 mg every 3weeks. In EP, pts with ICIs naive (Cohort A) or ICIs refractory (Cohort B) for adv or metastatic EC harboring FGFR mRNA overexpression who have received at least one prior therapy with a fluorouracil and platinum-based drug received futibatinib plus pembrolizumab at the recommended dose (RD) determined in FP. Primary endpoint was dose-limiting toxicity (DLT) in FP and overall response rate (ORR) in EP; Secondary endpoints included treatment-related adverse events (TRAEs) and disease control rate (DCR). As of November 29, 2021, 11 pts in FP, 9 pts (Cohort A) and 10 pts (Cohort B) in EP were enrolled. No DLTs were observed in FP and the RD of futibatinib in combination with pembrolizumab was determined 20 mg QD. Most common TRAEs in FP (N=11; all grade, grade ≥3) were hyperphosphatemia (91%, 27%), nausea (36%, 0%) and diarrhea (27%, 0%). As results of the interim analysis in EP, confirmed partial responses (PRs) were observed in 4 pts with squamous cell carcinoma (sq) in Cohort A; ORR was 44% with DCR of 78%. In Cohort B, confirmed PRs were observed in 2 pts [1 sq pt; 1 adenocarcinoma (adeno) pt]; ORR was 20% with DCR of 60%. Futibatinib plus pembrolizumab showed well-tolerability and manageable safety profile in pts with adv or metastatic solid tumors. Preliminary antitumor activity was observed not only in ICIs naïve but also in ICIs refractory adv or metastatic EC pts regardless of sq and adeno. Enrollment in EP is ongoing including an additional cohort for ICIs naïve 1st line adv EC and ICIs refractory adv NSCLC pts.

1712P Usefulness of schlafen-11 expression level in cstage II/III esophageal squamous cell carcinoma

Schlafen-11 (SLFN-11) was recently identified as a predictive marker of platinum-based drugs. In Japan, neoadjuvant chemotherapy, consists of 5-fluorouracil and cisplatin (NAC-FP), followed by surgery is the standard therapy for patients (pts) with resectable esophageal squamous cell carcinoma (ESCC). However, the correlation between SLFN-11 expression level and prognosis in ESCC pts treated with NAC-FP is unclear.

Puerarin inhibits EMT induced by oxaliplatin via targeting carbonic anhydrase XII.

Puerarin is a flavonoid molecule that widely exists in various plants. Puerarin has been reported to exhibit anti-tumor effects in various cancers. However, its exact underlying pharmacological mechanism is unclear. This study evaluated the anticancer effect of puerarin combined with oxaliplatin (OXA) in vitro and in vivo. Our results indicated that puerarin can reverse platinum-based anti-cancer drug resistance, and enhance the OXA’s anticancer effects on breast cancer. Furthermore, puerarin can inhibit migration and reverse the epithelial-mesenchymal transition (EMT) induced by low-dose OXA. Further studies showed that the carbonic anhydrase (CA) XII is a potential target of puerarin. In conclusion, puerarin is expected to become an adjuvant chemotherapy drug and potentially become one of the medicated foods for breast cancer patients.