Novel Treatment Developed for T-Cell Leukemias and Lymphomas

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A novel treatment for leukemias and lymphomas that arise from immune system T cells, developed by investigators at the Johns Hopkins Kimmel Cancer Center and its Ludwig Center and Lustgarten Laboratory, was found to be effective at killing these cancers in mice bearing human T-cell tumors.

The therapy, an antibody-drug conjugate (ADC), combines an antibody that targets a protein called TRBC1 expressed on the surface of T-cell cancers with an anti-cancer drug, called SG3249. The ADC works by using the antibody to seek out the cancer cells that express TRBC1. Then, those cancer cells ingest the ADC, where SG3249 is released and kills the cancer cells. A description of the work was published in Nature.

Each year, about 100,000 patients worldwide are affected by T-cell leukemias and lymphomas. Adults with relapsed T-cell cancers have limited therapeutic options and ﬁve-year survival rates of 7–38%.

“Developing treatments for T-cell leukemias and lymphomas is much more difﬁcult than for leukemias and lymphomas arising from immune system B cells,” explains senior study author Suman Paul, MBBS, PhD, an assistant professor of oncology at the Johns Hopkins University School of Medicine. Effective therapies for B-cell cancers wipe out both cancerous and noncancerous B cells, but patients still do well even without the immune system B cells that help ﬁght infections. However, if similar approaches are used and a treatment wipes out both normal and cancerous T cells, it would leave patients without a functioning immune system and at high risk of dying from infections.

“Not much drug development has happened in this space of T-cell leukemias and lymphomas,” Paul says. “We need new therapies for these cancers, but whatever therapies we develop in the space have to be cancer-speciﬁc. We have to preserve some of the normal T cells and wipe out cancerous T cells at the same time.”

T-cell cancers express either TRBC1 or TRBC2, while normal T cells express a mix of TRBC1 and TRBC2. Therefore, selective targeting of TRBC1 can potentially eradicate the normal and cancerous T cells expressing TRBC1 while preserving normal T cells expressing TRBC2. A recent clinical trial conducted elsewhere attempted to target TRBC1 cancers using chimeric antigen receptor (CAR) T-cell therapy. These CAR T cells are genetically engineered T cells that bind to and kill TRBC1 cells. CAR T-cell therapies are FDA-approved treatment options used in several B-cell cancers. However, after administering the TRBC1-targeting CAR T cell therapy in human patients, trial investigators reported that the CAR T cells were not persisting inside the patients. Such persistence is required for effective cancer cell-killing. Interested to understand why, Paul and colleagues found that the CAR T cells targeting TRBC1 could be killed by normal T cells, limiting their persistence.

This lack of CAR T-cell persistence led the team to try TRBC1 targeting with the use of antibody-drug conjugates. Paul and colleagues tried two different formulations of ADCs in mouse models of T-cell cancers. After a single injection of one formulation of the treatment, the cancers initially regressed but then recurred. After a single treatment with the anti-TRBC1-SG3249 ADC combination, investigators observed signs of cancer elimination within seven days and the cancers were eventually undetectable, with no recurrences. “The tumors didn’t come back, and we followed the mice for more than 200 days,” Paul explains.

The treatment was able to eliminate the cancer while preserving half of the remaining normal T cells. “The residual normal T cells should be sufﬁcient to maintain some immune system protection against infectious diseases,” Paul says.

“Witnessing the successful elimination of T-cell cancers while sparing normal T cells in preclinical models was truly gratifying,” adds Jiaxin Ge, a co-author of the study and third-year Ph.D. student in the Ludwig Center. “We believe this approach has the potential to address a critical unmet need in oncology, and we’re committed to advancing it through further research.”

Tushar Nichakawade, ﬁrst author on the study and a fourth-year PhD student at the Ludwig Center, says, “There are so many lessons to learn from the clinic and it has been exciting to be a part of the iterative process of drug discovery. Every therapy has its pros and cons, but the preclinical efﬁcacy of our ADC gives me hope that it can make a difference for patients suffering from these terrible cancers.”

Biologic Drug-Device Combination Immunotherapy for mCRPC Shows Promise

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SYNC-T, an investigational therapy that combines a device-induced vaccination at the tumor site with intratumoral infusion of a multitarget biologic drug, led to numerous clinical responses in patients with metastatic castrate-resistant prostate cancer (mCRPC). The results were reported at the American Association for Cancer Research (AACR) Annual Meeting 2024.

Patients with mCRPC—prostate cancer that does not respond to hormone therapies—have few treatment options and a high mortality rate, according to Charles Link, MD, an adjunct professor at Lankenau Institute for Medical Research, part of Main Line Health, and a cofounder and executive chairman of Syncromune. Prostate cancer has an immunologically “cold” tumor microenvironment. This has presented challenges for existing immunotherapies, which have exhibited low response rates and high toxicity in patients with prostate cancer.

Link and colleagues developed a novel treatment approach to stimulate a systemic antitumor immune response for mCRPC. Their therapy, called SYNC-T, first uses a probe that is inserted directly into the primary or metastatic tumor to freeze a portion of the tumor, which causes the tumor cells to fracture (oncolysis) and release immune-stimulating neoantigens. In essence, this method generates a personalized in situ neoantigen cancer vaccine that serves to activate the immune system, Link explained.

Link added that the imaging and procedural techniques for inserting a probe into the prostate are similar to the methods routinely used by urologists to conduct prostate biopsies. Immediately following the oncolysis step, an investigational multitarget biologic drug called SV-102—which is a fixed-dose drug comprised of active pharmaceutical ingredients: an anti-PD-1 antibody, an anti-CTLA4 antibody, a CD40 agonist, and a TLR9 agonist—is infused into the area of lysis in the tumor.

“SV-102 simultaneously blocks two distinct mechanisms of immune suppression and activates two distinct mechanisms of immune enhancement, allowing the vaccine-induced T cells to activate and mount a systemic antitumor immune response,” said Link.

The safety and efficacy of SYNC-T were evaluated in a phase I clinical trial, which enrolled 15 patients (12 patients with mCRPC and three patients with metastatic prostate cancer who opted out of hormone therapy), 13 of which have been evaluated for response. Sixty percent of patients identified as white, 33% as Hispanic, and 7% as Black. The median age was 61 years.

Of the 13 evaluable patients, 11 experienced an objective response, with five complete responses and six partial responses). The other two evaluable patients had stable disease at the time of data analysis. Six patients experienced mild to moderate treatment-related adverse events, including fever, rigors, fatigue, diaphoresis, hematuria, urinary tract infection, acute urinary retention, and hepatic enzyme elevation.

“The toxicity of SYNC-T appears to be much lower than what has been observed previously with intravenous immunotherapy for prostate cancer,” Link noted.

“Our results indicate that SYNC-T is associated with a high response rate without generating severe toxicity in this initial group of patients, which opens up opportunities to expand the role of immunotherapy in mCRPC,” he summarized. “Further, this approach uses standard procedures already employed by urologists and radiologists, which means the treatment could potentially be rapidly adopted by treating physicians.”

Limitations of the study include the small sample size, short follow-up time, and the single-arm design.

Agonist Antibodies for Cancer Immunotherapy: History, Hopes, and Challenges

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Abstract

Immunotherapy is among the most promising new treatment modalities to arise over the last two decades; antibody drugs are delivering immunotherapy to millions of patients with many different types of cancer. Initial success with antibody therapeutics came in the form of direct targeting or cytotoxic antibodies, such as rituximab and trastuzumab, which bind directly to tumor cells to elicit their destruction. These were followed by immunomodulatory antibodies that elicit antitumor responses by either stimulating immune cells or relieving tumor-mediated suppression. By far the most successful approach in the clinic to date has been relieving immune suppression, with immune checkpoint blockade now a standard approach in the treatment of many cancer types. Despite equivalent and sometimes even more impressive effects in preclinical models, agonist antibodies designed to stimulate the immune system have lagged behind in their clinical translation. In this review, we document the main receptors that have been targeted by agonist antibodies, consider the various approaches that have been evaluated to date, detail what we have learned, and consider how their anticancer potential can be unlocked.

Ribociclib plus Endocrine Therapy in Early Breast Cancer

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Abstract

BACKGROUND

Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear.

METHODS

In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease–free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease–free survival was evaluated with the use of the Kaplan–Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy.

RESULTS

As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease–free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease–free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P=0.003). Secondary end points — distant disease–free survival and recurrence-free survival — also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals.

CONCLUSIONS

Ribociclib plus an NSAI significantly improved invasive disease–free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer.

Oral targeted therapy for the treatment of non–small cell lung carcinoma

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KEY POINTS

Targeted cancer therapies are a group of oral medications directed at tumours harbouring specific driver mutations that occur in a subset of patients with cancer.
Around one-third to one-half of patients with advanced non–small cell lung carcinoma may harbour an actionable mutation, which can be identified from molecular analysis of a biopsy or surgical specimen.
Patients treated with targeted therapy generally have better symptom control, response rates (i.e., shrinking tumours), and overall survival than those treated with conventional chemotherapy.
Targeted therapy is typically well tolerated and does not carry the same risks of emesis, alopecia, immunosuppression, and febrile neutropenia as chemotherapy.

Lung cancer is the leading cause of cancer-related death in Canada, with non–small cell lung carcinoma (NSCLC) making up 85% of cases.1 Lung cancer has been associated with a poor prognosis, particularly for patients with metastatic disease. Since Health Canada’s initial approval of gefitinib in patients with advanced NSCLC in 2003, targeted therapies have emerged as an important treatment option for patients and are now widely used in clinical practice.

What is targeted therapy?

Targeted therapies are a group of personalized anti-cancer medications. While chemotherapy attacks all rapidly dividing cells, targeted therapies select for cancer cells that harbour specific genomic driver alterations. Driver alterations are the principal trigger of growth for cancer cells, and many of these driver alterations now have matched targeted therapies. About 30%–50% of patients with NSCLC harbour a tumour-driver alteration and about 50%–75% of these are targetable.2 The prevalence of specific driver alterations varies by patient age, degree of tobacco exposure, ethnicity, and histology.2

Small-molecule tyrosine kinase inhibitors are the most common type of targeted therapy used in the treatment of NSCLC, and they work by inhibiting tyrosine kinase enzymes. Tyrosine kinase enzymes are membrane-spanning proteins made up of an extracellular (ligand-binding domain) and an intracellular kinase domain. Under normal physiologic conditions, ligand binding of the extracellular domain results in phosphorylation of downstream proteins, leading to their activation in a highly regulated fashion. The presence of an activating oncogenic alteration causes the tyrosine kinase enzyme to become constitutively active (i.e., does not need ligand binding to be in the “on” position), which drives cancer cell growth and proliferation. Targeted therapies treat cancer by inhibiting these overactive tyrosine kinase enzymes. Practically, targeted therapies are oral medications that can be taken at home without the number of hospital attendances associated with intravenous therapies.

Who is eligible for targeted therapy?

To assess whether targeted therapy is a suitable option, patients must undergo molecular profiling of their tumour. Molecular testing can be performed on most biopsy specimens, often on the same sample used to make the initial histopathologic cancer diagnosis. In some instances, especially when the procurement of a biopsy is difficult, analysis of circulating tumour DNA in the patient’s blood can also identify tumour-related gene alterations. Modern next-generation sequencing techniques can test for multiple alterations in parallel. Next-generation sequencing capacity has rapidly improved in Canada in recent years, although the turnaround time for molecular testing varies, with the ideal scenario being 1–2 weeks from biopsy to result. Figure 1 depicts the workflow in assessing candidacy for targeted therapy.

A schematic depicting the workflow of assessing patients for and prescribing targeted therapy. (A) The patient undergoes a biopsy for histopathologic diagnosis of non–small cell lung carcinoma. (B) Tumour tissue is sent for molecular analysis. If a driver mutation is detected, the patient may be a candidate for a targeted agent. (C) The patient reviews the results with their oncologist and consents to targeted therapy. (D) The prescription can be filled at an outpatient pharmacy, and targeted therapy can be taken at home.

Molecular testing is performed reflexively (i.e., ordered by the pathologist) for newly diagnosed non-squamous lung cancers at most institutions, while others require a requisition from the oncologist. Many Canadian cancer centres offer in-house molecular testing, but others will send tissue samples externally for molecular analysis. All standard-of-care molecular testing can be performed in Canada.

What is the evidence of benefit?

Metastatic NSCLC is associated with poor clinical outcomes. Efficacy of cancer treatments is generally measured by response rates (proportion of patients with substantial tumour shrinkage), quality of life, and overall survival. Before the introduction of targeted therapy in the management of metastatic lung cancer, patients treated with chemotherapy had a median survival of less than 9 months, with response rates in the range of 25%–35%; only 10% of patients survived to the 2-year mark.3

Targeted therapy has improved outcomes tremendously, whereby most patients receiving a targeted drug have major tumour shrinkage, symptom improvement, and longer survival. 4 In the context of metastatic cancer, targeted therapies are given with palliative intent, with the goal improving quality of life and overall survival rather than to cure cancer. However, 2 targeted therapies, alectinib and osimertinib, have been shown to significantly decrease rates of recurrence when given as adjuvant treatment after surgery among patients with non-metastatic disease.5^,6

Ten different alterations have been identified, treated with 20 effective targeted therapies (Table 1).7 Mutations in the epidermal growth factor receptor (EGFR) gene were initially discovered in 2004, and are the most common mutations identified in NSCLC. Among patients harbouring a classic EGFR mutation, osimertinib, an EGFR kinase inhibitor, approved by Health Canada for the treatment of non-metastatic NSCLC in 2021, has proven to be the optimal agent, with a median overall survival of 38.6 months, compared with 31.8 months for people receiving older generations of EGFR kinase inhibitors.8 Patients with metastatic NSCLC involving anaplastic lymphoma kinase (ALK) translocations have a 5-year survival rate of more than 60% when treated with alectinib, compared with 45.5% among those treated with crizotinib, the first ALK inhibitor approved.9 For patients with RET translocations treated with selpercatinib, 84% of patients had a major tumour shrinkage, with the response being durable for close to 2 years, although no comparator arm was used in this single-arm, phase 2 study.10 Figure 2 shows the radiographic response of a patient harbouring a RET mutation treated with selpercatinib. Targeted agents directed at KRAS, BRAF, MET, NTRK, ROS1, and HER2 have also shown meaningful clinical benefit, although in some cases, the data are too recent to report 5-year survival rates.2^,4 Patients can receive targeted therapy at home with remarkable response rates and the ability to maintain quality of life and symptom control, in addition to better odds at long-term survival.11^–13

List of Health Canada–approved targeted agents by the genes harbouring the sensitizing alteration7

Figure 2:

Axial computed tomography (CT) chest scans of a female patient in her late 80s, diagnosed with metastatic lung adenocarcinoma harbouring a RET rearrangement (ERC1 exon 17 to RET exon 12) treated with selpercatinib (A) at the time of diagnosis and (B) 9 months after starting therapy, showing radiographic response below the aortic arch.

The efficacy of targeted therapies is heterogeneous and varies depending on the specific drug and target protein. This results in variable magnitudes of benefit with regard to response rate, progression-free survival, and overall survival. Given the rarity of certain actionable mutations, many targeted agents have been studied only in single-arm, phase 2 clinical trials.

What are the harms?

Targeted therapies have more favourable adverse effect profiles than chemotherapy. Adverse effects are specific to the agent used and the protein being inhibited. They are usually mild and can typically be managed supportively. Table 2 provides an overview of adverse effects related to targeted therapy. If symptoms persist or affect a patient’s quality of life or functionality, dose reductions are usually considered as the next step in management. Severe or life-threatening adverse effects are uncommon; thus, the risk–benefit balance for targeted therapies almost always favours treatment, unlike traditional cytotoxic chemotherapy. Unlike chemotherapy, targeted therapies do not cause notable immunosuppression and most patients presenting with fever can be managed as per routine clinical practice. Most targeted agents require regular blood work to monitor blood counts and electrolytes, as well as kidney and liver function. Some agents may require cardiac testing (e.g., electrocardiography, echocardiography). This monitoring is typically organized by the patient’s oncologist

Adverse effects related to targeted therapy classes, grouped by their target gene^*

What are the resource implications and how is targeted therapy accessed?

Targeted therapies are usually more costly than chemotherapy and sometimes more than immunotherapy. Using estimates from wholesale prices in the United States, the average cost of targeted therapy is US$5000–US$10 000 monthly. Treatments are usually continuous until signs of cancer progression in the metastatic setting. 14^,15 However, costs vary considerably between agents, and are much lower in Canada than the list price as the prices paid by provinces are heavily discounted based on negotiation by the pan-Canadian Pharmaceutical Alliance, although these negotiated prices are not publicly available. In general, the costs of targeted therapies are likely to decrease as more agents expire from patent and become available as generic medications.

Interprovincial differences to access these drugs exist, leading to disparities across Canada. For instance, oral cancer drugs are funded the same way as intravenous drugs in some provinces (e.g., British Columbia), but through different pathways in other provinces (e.g., Ontario). Accessing therapies when they are not provincially funded is challenging. Options include public or private insurance, private pay, and compassionate access or co-pay programs through pharmaceutical companies.

What can be expected in the future?

Targeted therapy is the standard of care for patients with metastatic NSCLC driven by alterations in select oncogenes. In the future, these agents are likely to be used in earlier stages of disease with the aim of improving cure rates. Further expansion of targeted therapies will be observed as molecular testing becomes part of routine practice, as more patients with targetable mutations will be identified. More targetable alterations are being discovered. From the first mutation (EGFR) in 2004, to the second (ALK fusion) in 2009, 10 alterations have been identified, with other candidates in discovery. In addition, as mechanisms of resistance to targeted therapies are better understood, new agents are being developed that target resistant cancer cell clones.

Anlotinib inhibits growth of human esophageal cancer TE-1 cells by negative regulating PI3K/Akt signaling pathway

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Abstract

Anlotinib is effective in treatment of many kinds of malignant cancer, but its antineoplastic effects on esophageal cancer remains unclear. This study aims to investigate its impact on esophageal cancer and the underlying mechanisms. Anlotiniband 5-fluorouracil + cisplatin (5-FU + DDP) was administered separately to human esophageal cancer TE- 1 cells tumor xenograft mouse models every 3 days. Tumor size and body weight were measured before each treatment and at the end of the experiment. In vitro studies were conducted using TE- 1 cells to examine the effects of Anlotinib. Cell viability, migration, proliferation, apoptosis, cell cycle, their regulatory proteins and the transcriptomic changes were analyzed. Anlotinib reduced tumor size, tumor weight, and the ratio of tumor weight to body weight in vivo. It decreased the viability of TE- 1 cells, with a 50% growth-inhibitory concentration of 9.454 μM for 24 h, induced apoptosis, and arrested TE- 1 cell cycle in the S phase. It inhibited migration and proliferation while negatively regulating the PI3K/Akt signaling pathway. Enhanced expressions of P21, Bax, and lowered expressions of cyclin A1, cyclin B1, CDK1, PI3K, Akt, p-Akt, and Bcl-2 were observed after Anlotinib treatment. Anlotinib exhibits antineoplastic activity against human esophageal cancer TE- 1 cells by negatively regulating the PI3K/Akt signaling pathway, consequently altering the expressions of proteins related to proliferation, apoptosis, and the cell cycle.

1 Introduction

Esophageal cancer (EC) is characterized by high morbidity and mortality [1, 2]. It consists of two major histologic subtypes: adenocarcinoma and squamous cell carcinoma(SCC), with SCC being the predominant subtype. EC exhibits significant regional variations globally. Certain regions in Asia, East Africa, and South America, such as China, Iran, Kenya, and Brazil, have higher incidence rates of esophageal cancer. This is associated with local factors such as diet, lifestyle, cooking methods, food choices, and environmental factors. Despite significant advancements in surgery, preoperative chemotherapy, and radiotherapy, the survival rate remains low, with a 5-year survival rate ranging from 15 to 20%, and a median survival time of 1.5 years [3]. This is despite the considerable progress in surgery, preoperative chemotherapy, and radiotherapy. The therapy regimen primarily depends on the physical condition and tumor stage, typically classified by the TMN stage of EC patients. Chemotherapy is widely applied to patients who are not suitable for surgery.

Anlotinib is a recently approved chemotherapeutic agent that has gained approval for the treatment of advanced non-small-cell lung cancer as a third-line therapy option in China [4, 5]. It functions as a multikinase inhibitor, targeting vascular endothelial growth factor receptors (EGFR) 1–3, fibroblast growth factor receptors 1–4, the platelet-derived growth factor receptor, and the stem cell factor receptor to inhibit neoangiogenesis and tumor progression [6,7,8]. Anlotinib also inhibits the activity of basic fibroblast growth factor receptor (bFGFR). bFGFR is another crucial receptor associated with tumor growth and angiogenesis. By affecting the bFGFR signaling pathway, Anlotinib can regulate cell growth, differentiation, and migration, thereby influencing the development of tumors. Anlotinib has been found to induce apoptosis in tumor cells, which refers to programmed cell death. This is an essential part of the normal cell lifecycle but is often disrupted in tumors. By prompting tumor cells to undergo programmed cell death, Anlotinib helps inhibit the growth of tumors.

Furthermore, studies have demonstrated the efficacy of anlotinib against intrahepatic cholangiocarcinoma [9], soft tissue sarcoma [10], thyroid cancer [11], and colorectal cancer [12]. It exhibited notable therapeutic effects against esophageal squamous cell carcinoma (ESCC) on patient-derived xenograft models when combined with chemoradiotherapy, while the exact mechanism remains unclear. Therefore, our study was designed to investigate the efficacy and underlying mechanism of anlotinibon ESCC using tumor xenograft animal models and TE- 1 cells.

Discussion

In China, approximately 240,000 new cases of EC are diagnosed each year, with EC ranking as the fourth leading cause of cancer-related mortality [13,14,15]. Many patients receive diagnoses at advanced stages, leading to 5-year survival rate of merely 5%. The discovery of new medicines for treating EC is an imperative need. Current studies on anlotinib have mostly focused on its anticancer activity against advanced non-small-cell lung cancer [7]. Jingzhen Shi combined anlotinib with chemoradiotherapy to treat EC with good achievements [16]. These results have inspired us to investigate the underlying mechanisms behind anlotinib’s effects on EC.

In our study, anlotinib demonstrated excellent antineoplastic activity against EC in vivo, with less body weight loss in comparison to the 5-FU + DDP treatment. This effect was corroborated by the outcomes observed in the TE-1 cell line, where anlotinib exhibited an IC50 value of 9.454 μM. Furthermore, anlotinib induced TE- 1 cell apoptosis and notably arrested the cell cycle in the S phase, thereby inhibiting migration and proliferation in a dose-dependent manner. These findings indicate that Anlotinib has potential therapeutic capabilities against esophageal cancer, exhibiting significant anti-tumor effects both in vivo and in vitro. Furthermore, Anlotinib effectively inhibits the migration and proliferation of esophageal cancer cells by inducing apoptosis and arresting the cell cycle, providing important evidence for its further research and clinical application as an anti-cancer treatment.

The PI3K/Akt signaling pathway is a crucial cellular signaling cascade involved in regulating various biological processes such as cell survival, proliferation, differentiation, and metabolism [17, 18]. Its name derives from two key proteins involved in the pathway: phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), also known as protein kinase B activated kinase (PKB). PI3K is an enzyme that catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) on the cell membrane [19, 20]. Upon activation, PIP3 can bind and activate Akt, thereby initiating downstream signaling cascades. Akt, a critical regulatory protein in the PI3K/Akt pathway, promotes cell survival and proliferation while inhibiting apoptosis. Akt exerts its effects by phosphorylating various cellular factors, cell cycle proteins, and transcription factors, thereby modulating cellular physiology. Aberrant activation of the PI3K/Akt signaling pathway is closely associated with the onset and progression of various diseases, including cancer [21, 22]. PI3K/Akt signaling pathway plays a crucial role in the proliferation, survival, and invasion of tumor cells [23, 24] including TE- 1 cells [25,26,27]. The activation of PI3K promotes Akt to be phosphorylated intop-Akt, p-Akt acts on its downstream proteins to enhance TE-1 cell survival, proliferation and invasion. The PI3K/Akt signaling pathway can also participate in cell survival and inflammatory responses by activating NF-κB (nuclear factor-kappa B). NF-κB is a transcription factor that regulates the expression of various genes, including those associated with cell survival, proliferation, and immune responses. The excessive activation of the PI3K/Akt signaling pathway is closely associated with the occurrence and development of various diseases, including cancer, diabetes, and neurological disorders. Therefore, this signaling pathway has become a crucial target for drug development, and drugs targeting its abnormal activation are being investigated for the treatment of diseases such as cancer. Our findings indicated that anlotinib treatment notably downregulated PI3K, Akt, and p-Akt, aligning with the results of other studies [9, 10].

Survivin plays a significant role in regulating cell division, apoptosis (programmed cell death), and cell survival. It is a member of the inhibitor of apoptosis (IAP) family of proteins, which are characterized by their ability to inhibit apoptosis and promote cell survival [28, 29]. Survivin is overexpressed in various types of human tumor cells, including lung cancer, breast cancers, EC, as well as TE-1 cells, as indicated by our research. The suppression of survivin promotes tumor cells apoptosis and enhances radiosensitivity of esophageal cancer cells [30,31,32]. Besides, Bax serves as an apoptosis promoter, while Bcl-2, an important homolog of Bax, plays the inverse effects of Bax [33, 34]. Our results demonstrated that anlotinib treatment significantly promoted TE- 1 cells apoptosis through suppression of survivin, Bcl-2 and enhancement of Bax expressions. By understanding how Anlotinib regulates key genes such as survivin, Bcl-2, and Bax to promote apoptosis in TE-1 cells, we can gain deeper insights into its mechanism of action in anticancer processes, which can guide further clinical research and the development of more effective treatment strategies.

Cyclin A1 is the product of CCNA1 gene expression. Except Akt as one of the two central proteins affectd by anlotinib treatment, Cyclin A1 was the other central protein which interacting with other proteins to regulate cell cycle. Cyclin A1 which working together with cyclinB1 to promote S to G2/M phase transition. The combination of cyclin A1 or cyclinB1 to CDK1 triggers cell cycle into mitosis [35,36,37]. P21 is currently recognized as a potent universal CDK inhibitor which forms complexes with CDKs and cyclins to arrest cell cycle [38, 39]. Anlotinib negatively regulated cyclin A1, cyclin B1 and CDK1 expressions while positively up regulated P21 expression in TE- 1 cells. These observations elucidate the mechanism underlying its effects on cell cycle arrest.

This article has some shortcomings. Firstly, although the study elucidated the negative regulation of the PI3K/Akt signaling pathway by Anlotinib, the underlying mechanisms of this regulation have not been fully explored. Further mechanistic studies are needed to analyze the molecular pathways involved and confirm the observed effects. Secondly, TE-1 cells may not fully represent the heterogeneity of esophageal cancer. Including other esophageal cancer cell lines or samples originating from patients could provide a more comprehensive understanding of the effects of Anlotinib in different molecular subtypes of the disease.

5 Conclusions

Anlotinib can induce apoptosis and cell cycle arrest, inhibit migration and proliferation of TE- 1 cells by negatively regulating PI3K/Akt signaling pathway, and consequently regulating expressions of apoptosis- related and cell-cycle-related proteins. The detailed underlying mechanism may be further elucidated in future research.

Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma

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