Treatment Modality For Cancer Research Articles

Crosstalk between Oxidative Stress and Inflammation Induced by Ionizing Radiation in Healthy and Cancerous Cells.

Radiotherapy (RT) is a unique modality in cancer treatment with no replacement in many cases and uses a tumoricidal dose of various ionizing radiation types to kill cancer cells. It causes oxidative stress through reactive oxygen species (ROS) production or the destruction of antioxidant systems. On the other hand, RT stimulates the immune system both directly and indirectly by releasing danger signals from stress-exposed and dying cells. Oxidative stress and inflammation are two reciprocal and closely related mechanisms, one induced and involved by the other. ROS regulates the intracellular signal transduction pathways, which participate in the activation and expression of pro-inflammatory genes. Reciprocally, inflammatory cells release ROS and immune system mediators during the inflammation process, which drive the induction of oxidative stress. Oxidative stress or inflammation-induced damages can result in cell death (CD) or survival mechanisms that may be destructive for normal cells or beneficial for cancerous cells. The present study has focused on the radioprotection of those agents with binary effects of antioxidant and anti-inflammatory mechanisms in ionizing radiation (IR)-induced CD.

Energy-storing DNA-based hydrogel remodels tumor microenvironments for laser-free photodynamic immunotherapy

Photodynamic therapy (PDT) is a promising modality for cancer treatment. However, limited tissue penetration of external radiation and complicated tumor microenvironments (TMEs) restrict the antitumor efficiency of PDT. Herein, we report an energy-storing DNA-based hydrogel, which enables tumor-selective PDT without external radiation and regulates TMEs to achieve boosted PDT-mediated tumor immunotherapy. The system is constructed with two ultralong single-stranded DNA chains, which programmed partial complementary sequences and repeated G-quadruplex forming AS1411 aptamer for photosensitizer loading via hydrophobic interactions and π-π stacking. Then, energy-storing persistent luminescent nanoparticles are incorporated to sensitize PDT selectively at tumor site without external irradiation, generating tumor antigen to agitate antitumor immune response. The system catalytically generates O2 to alleviate hypoxia and releases inhibitors to reverse the IDO-related immunosuppression, synergistically remodeling the TMEs. In the mouse model of breast cancer, this hydrogel shows a remarkable tumor suppression rate of 78.3 %. Our study represents a new paradigm of photodynamic immunotherapy against cancer by combining laser-free fashion and TMEs remodeling.

Facile Synthesis of a Multifunctional Porous Organic Polymer Nanosonosensitizer (mHM@HMME) for Enhanced Cancer Sonodynamic Therapy.

Sonodynamic therapy (SDT), which involves the activation of sonosensitizers to generate cytotoxic reactive oxygen species under ultrasound irradiation, is a promising noninvasive modality for cancer treatment. However, the clinical translational application of SDT is impeded by the lack of efficient sonosensitizers, the inefficient accumulation of sonosensitizers at tumor sites, and the complicated immunosuppressive tumor microenvironment. Herein, we developed a facilely synthesized multifunctional porous organic polymer nanosonosensitizer (mHM@HMME) for enhanced SDT. Specifically, mHM@HMME nanosonosensitizers were prepared by incorporating chemotherapeutic mitoxantrone into the one-step synthesis process of disulfide bond containing porous organic polymers, followed by loading with organic sonosensitizer (HMME) and camouflaging with a cancer cell membrane. Due to the cancer cell membrane camouflage, this multifunctional mHM@HMME nanosonosensitizer showed prolonged blood circulation and tumor targeting aggregation. Under ultrasound irradiation, the mHM@HMME nanosonosensitizer exhibited a satisfactory SDT performance both in vitro and in vivo. Moreover, the potent SDT combined with glutathione-responsive drug release in tumor cells induced robust immunogenic cell death to enhance the antitumor effect of SDT in turn. Overall, this facilely synthesized multifunctional mHM@HMME nanosonosensitizer shows great potential application in enhanced SDT.

"Current", "heated rods", and "hot vapour": why patients refuse radiotherapy as a treatment modality for cancer in northern Sri Lanka.

Significant proportions of patients either refuse or discontinue radiotherapy, even in the curative setting, leading to poor clinical outcomes. This study explores patient perceptions that underlie decisions to refuse/discontinue radiotherapy at a cancer care facility in northern Sri Lanka. An exploratory descriptive qualitative study was carried out among 14 purposively selected patients with cancer who refused/discontinued radiotherapy. In-depth semi-structured interviews were transcribed in Tamil, translated into English, coded, and thematically analyzed. All participants referred to radiotherapy as "current" with several understanding the procedure to involve electricity, heat, or hot vapour. Many pointed to gaps in information provided by healthcare providers, who were perceived to focus on side effects without explaining the procedure. In the absence of these crucial details, patients relied on family members and acquaintances for information, often based on second or third-hand accounts of experiences with radiotherapy. Many felt pressured by family to refuse radiation, feared radiation, or felt ashamed to ask questions, while for others COVID-19 was an impediment. All but three participants regretted their decision, claiming they would recommend radiation to patients with cancer, especially when it is offered with curative intent. Patients with cancer who refused/discontinued radiation therapy have significant information needs. While human resource deficits need to be addressed in low-resource settings like northern Sri Lanka, providing better supportive cancer care could improve clinical outcomes and save healthcare resources that would otherwise be wasted on patient preparation for radiotherapy.

Trends in Early-Stage Cervical Cancer Management in the US: A National Cancer Database Analysis.

The Laparoscopic Approach to Cervical Cancer (LACC) trial was published in 2018 and demonstrated that minimally invasive surgery (MIS) yields inferior survival outcomes in early-stage cervical cancer compared to open surgery. This study investigates how the results of the LACC trial have impacted the selection of the primary treatment modality and adjuvant radiation utilization in early-stage cervical cancer. Using the National Cancer Database (NCDB), we compared patients with stage IA2-IB1 cervical cancer before (1/2016-12/2017) and after (1/2019-12/2020) the LACC trial. A total of 7930 patients were included: 4609 before and 3321 after the LACC trial. There was a decline in MIS usage from 67% pre-LACC to 35% thereafter (p < 0.001). In both the pre- and post-LACC periods, patients undergoing radical MIS more frequently had small volume disease (pre-LACC tumors ≤ 2 cm, 48% MIS vs. 41% open, p = 0.023; post-LACC stage IA2, 22% vs. 15%, p = 0.002). Pre-LACC, MIS radical hysterectomy was associated with White race (82% vs. 77%, p = 0.001) and private insurance (63% vs. 54%, p = 0.004), while there was no difference in socioeconomic factors in the post-LACC period. Although the proportion of patients treated with primary chemoradiation remained stable, the post-LACC cohort had a younger median age (52.47 vs. 56.37, p = 0.005) and more microscopic disease cases (13% vs. 5.4%, p = 0.002). There was no difference in the rate of radiation after radical hysterectomy before and after the trial (26% vs. 24%, p = 0.3). Conclusions: Post-LACC, patients were less likely to undergo MIS but received adjuvant radiation at similar rates, and primary chemoradiation patients were younger and more likely to have microscopic disease.

An end-to-end deep convolutional neural network-based dose engine for parotid gland cancer seed implant brachytherapy.

Seed implant brachytherapy (SIBT) is a promising treatment modality for parotid gland cancers (PGCs). However, the current clinical standard dose calculation method based on the American Association of Physicists in Medicine (AAPM) Task Group 43 (TG-43) Report oversimplifies patient anatomy as a homogeneous water phantom medium, leading to significant dose calculation errors due to heterogeneity surrounding the parotid gland. Monte Carlo Simulation (MCS) can yield accurate dose distributions but the long computation time hinders its wide application in clinical practice. This paper aims to develop an end-to-end deep convolutional neural network-based dose engine (DCNN-DE) to achieve fast and accurate dose calculation for PGC SIBT. A DCNN model was trained using the patient's CT images and TG-43-based dose maps as inputs, with the corresponding MCS-based dose maps as the ground truth. The DCNN model was enhanced based on our previously proposed model by incorporating attention gates (AGs) and large kernel convolutions. Training and evaluation of the model were performed using a dataset comprising 188 PGC I-125 SIBT patient cases, and its transferability was tested on an additional 16 non-PGC head and neck cancers (HNCs) I-125 SIBT patient cases. Comparison studies were conducted to validate the superiority of the enhanced model over the original one and compare their overall performance. On the PGC testing dataset, the DCNN-DE demonstrated the ability to generate accurate dose maps, with percentage absolute errors (PAEs) of 0.67%±0.47% for clinical target volume (CTV) D90 and 1.04%±1.33% for skin D0.1cc. The comparison studies revealed that incorporating AGs and large kernel convolutions resulted in 8.2% (p<0.001) and 3.1% (p<0.001) accuracy improvement, respectively, as measured by dose mean absolute error. On the non-PGC HNC dataset, the DCNN-DE exhibited good transferability, achieving a CTV D90 PAE of 1.88%±1.73%. The DCNN-DE can generate a dose map in less than 10 ms. We have developed and validated an end-to-end DCNN-DE for PGC SIBT. The proposed DCNN-DE enables fast and accurate dose calculation, making it suitable for application in the plan optimization and evaluation process of PGC SIBT.

Tumor targeted porphyrin-based metal–organic framework for photodynamic and checkpoint blockade immunotherapy

Photodynamic therapy (PDT) has become a promising approach and non-invasive modality for cancer treatment, however the therapeutic effect of PDT is limited in tumor metastasis and local recurrence. Herein, a tumor targeted nanomedicine (designated as PCN@HA) is constructed for enhanced PDT against tumors. By modified with hyaluronic acid (HA), which could target the CD44 receptor that expressed on the cancer cells, the targeting ability of PCN@HA has been enhanced. Under light irradiation, PCN@HA can produce cytotoxic singlet oxygen (1O2) and kill cancer cells, then eliminate tumors. Furthermore, PCN@HA exhibits fluorescence (FL)/ photoacoustic (PA) effects for multimodal imaging-guided cancer treatment. And PCN@HA-mediated PDT also can induce immunogenic cell death (ICD) and stimulate adaptive immune responses by releasing of tumor antigens. By combining with anti-PD-L1 checkpoint blockade therapy, it can not only effectively suppress the growth of primary tumor, but also inhibit the metastatic tumor growth.

Treatment Modalities for Non-Muscle Invasive Bladder Cancer: An Updated Review.

The landscape of treatment for non-muscle invasive bladder cancer is rapidly changing. A complete and careful transurethral resection is the mainstay of initial treatment and is followed by intravesical therapy in intermediate or high-risk cases. The standard of care is intravesical BCG. Many alternative or additive approaches to this are being explored. We divided this review into three relevant spaces to consider these novel treatment approaches: (1) low-risk disease, for which intravesical therapy is not usually considered, (2) BCG-naïve disease (i.e., considering alternatives to the standard therapy), and (3) BCG-unresponsive disease. We performed a review of published literature and summarized ongoing trials in the United States. Novel approaches that we explored include surgical techniques for resection, alterations in dwell time for intravesical therapy, delivery method and schedule of intravesical therapies, new intravesical therapy agents, and systemic therapies (especially immunotherapy). These are thoroughly outlined throughout this review article, and the numerous modalities being studied demonstrate significant promise for the future treatment of the expanding space of NMIBC.

A scoping review of the management of prostate cancer in Africa

Prostate cancer is one of the most frequently diagnosed cancers in menand a major cause of cancer-related deaths in men, globally. The managementof prostate cancer in Africa is unique; most patients present withadvanced disease as result of a largely under-developed healthcare delivery.However, due to the underdeveloped healthcare system in Africa,there are unique limitations to delivering these treatments. Thus, the needfor this scoping review on the management of prostate cancer in Africa.Aim: To give an account of the pattern of presentation, histological types,investigative and treatment modalities of prostate cancer in Africa. A literaturesearch through PubMed, Google Scholar, and African Journal Onlineon the management of prostate cancer in Africa was conducted. Results arethen reported according to the Preferred Reporting Items for SystematicReview and Meta-analyses extension for Scoping Review. Forty-three articlesfully satisfied the inclusion criteria and were used for this review.The commonest presentation of prostate cancer was lower urinarytract symptoms, followed by bone pain and urinary retention in that order.Adenocarcinoma was the commonest histological type for 98.5% of thestudy. A total 23.3% of patients had hormonal treatment which was the commonesttreatment option. Chemotherapy and open radical prostatectomywere used in 17.7 and 12.9% cases respectively. The use of robot-assistedradical prostatectomy was not an option of care noted in the review. Thefindings of this study highlight the need for integration of modern investigativemodalities and treatment options for prostate cancer in Africa.

Synergistic luminescent radicals and precursors as type-I photosensitizers for near-infrared fluorescence-guided tumor therapy

Near-infrared (NIR) fluorescence-guided photodynamic therapy (PDT) shows great potential as a cancer treatment modality. However, its application in solid tumors is limited by the scarcity of NIR molecules and the oxygen dependence of conventional photosensitizers. Here, two novel radical nanoparticles (TTM-3PDMAC:HTTM-3PDMAC@NPs and TTM-PDMAC:HTTM-PDMAC@NPs) are developed as type-I photosensitizers by combining luminescent radicals and their precursors. The unique encapsulation of these nanoparticles effectively addresses the limitations of radicals being insoluble and non-fluorescent in water, thus preserving the NIR emission of the radicals. Notably, the superoxide radicals generated by these nanoparticles upon light irradiation have been demonstrated to originate from both the radicals and their precursors. In vivo experiments demonstrated that TTM-3PDMAC:HTTM-3PDMAC@NPs exhibit significant efficacy in treating hypoxic tumor with minimal side effects. Overall, this PDT strategy based on synergistic combination of luminescent radicals and precursors provides novel insights for achieving accurate and efficient PDT under NIR fluorescence guidance.

Emodin induces ferroptosis in colorectal cancer through NCOA4-mediated ferritinophagy and NF-κb pathway inactivation.

Ferroptosis is a new programmed cell death characterized by iron-dependent lipid peroxidation. Targeting ferroptosis is considered a promising strategy for anti-cancer therapy. Recently, natural compound has gained increased attention for their advantage in cancer treatment, and the exploration of natural compounds as ferroptosis inducers offers a hopeful avenue for advancing cancer treatment modalities. Emodin is a natural anthraquinone derivative in many widely used Chinese medicinal herbs. In our previous study, we predicted that the anti-cancer effect of Emodin might related to ferroptosis by using RNA-seq in colorectal cancer (CRC). Thus, in this study, we aim to investigate the molecular mechanism underlying Emodin-mediated ferroptosis in CRC. Cell-based assays including CCK-8, colony formation, EdU, and Annexin V/PI staining were employed to assess Emodin's impact on cell proliferation and apoptosis. Furthermore, various techniques such as FerroOrange staining, C11-BODIPY 581/591 staining, iron, MDA, GSH detection assay and transmission electron microscopy were performed to examine the role of Emodin in ferroptosis. Additionally, specific NCOA4 knockdown cell lines were generated to elucidate the involvement of NCOA4 in Emodin-induced ferroptosis. Moreover, the effects of Emodin on ferroptosis were further confirmed through the application of inhibitors, including Ferrostatin-1, 3-MA, DFO, and PMA. As a results, Emodin inhibited proliferation and induced apoptosis in CRC cells. Emodin could decrease GSH content, xCT and GPX4 expression, meanwhile increasing ROS generation, MDA, and lipid peroxidation, and these effects could reverse by ferroptosis inhibitor, Ferostatin-1, iron chelator DFO, autophagy inhibitor 3-MA and NCOA4 silencing. Moreover, Emodin could inactivate NF-κb pathway, and PMA, an activator of NF-κb pathway could alleviate Emodin-induced ferroptosis in CRC cells. Xenograft mouse model also showed that Emodin suppressed tumor growth and induced ferroptosis in vivo. In conclusion, these results suggested that Emodin induced ferroptosis through NCOA4-mediated ferritinophagy by inactivating NF-κb pathway in CRC cells. These findings not only identified a novel role for Emodin in ferroptosis but also indicated that Emodin may be a valuable candidate for the development of an anti-cancer agent.

Radiotherapy Related Bowel and Bladder Toxicity after Prostate Cancer Irradiation

Background: Pelvic radiotherapy is a primary treatment modality for organ-confined prostate cancer and early-stage endometrial cancer. While effective in improving survival rates and reducing recurrence, it is associated with a range of side effects that can impact patient quality of life. Objective: The study aimed to assess the incidence, management, and resolution of acute and chronic side effects of pelvic radiotherapy in prostate and endometrial cancer patients, focusing on bowel and bladder functions. Methods: This single-center, observational study included 50 patients diagnosed with prostate or endometrial cancer who underwent pelvic radiotherapy with a dose of 66-70 Gy using a four-field technique on a linear accelerator. Patients were assessed for bladder and bowel dysfunction, with follow-up at 6, 12, and 18 months post-treatment. Statistical analysis involved univariate weighted distribution of response frequencies and paired t-tests for ordinal scale scores, using SPSS version 25 for data analysis. Results: Of the participants, 22% experienced dysuria, 64% reported bladder outlet obstruction, and 20% had constipation. Acute bowel symptoms like diarrhea occurred in 32%, and chronic proctitis developed in 22% of patients. Urinary symptoms appeared by the third week and generally resolved within weeks; however, bowel symptoms persisted longer but returned to baseline by 18 months post-treatment. Approximately 70% of patients reported good tolerance to radiotherapy. Conclusion: Pelvic radiotherapy is effective in treating prostate and endometrial cancers but requires management of transient side effects to improve patient outcomes. Advanced radiotherapy techniques such as IMRT and 3D CRT have shown potential in reducing these side effects, emphasizing the need for continuous technological advancements and patient-centered care in radiotherapy.

Abstract PO2-01-11: Demographic, Lifestyle, and Clinical Factors Associated with Early vs. Late Recurrence among Women with Early-Stage Estrogen Receptor-Positive Breast Cancer in the Prospective Pathways Study

Abstract Background: Although women diagnosed with early-stage estrogen receptor (ER)-positive breast cancer generally have a favorable prognosis, they face a lingering risk of late recurrence that can occur years to decades after diagnosis. Relatively little is known about the demographic, lifestyle, or clinical factors associated with the risk of late recurrence, or whether the associations differ between early vs. late recurrence. Methods: We performed a comprehensive analysis of factors related to early vs. late recurrence in early-stage ER-positive breast cancer in the Pathways Study, an established prospective cohort of women diagnosed with invasive breast cancer at Kaiser Permanente Northern California (KPNC) between 2006 and 2013. Recurrences were identified through monthly searches of the KPNC Cancer Registry, follow-up interviews with participants, and confirmation with electronic medical records. For this analysis, 2,473 women with stage I-IIB, ER-positive breast cancer were included, with ascertainment of recurrence and death through December 31, 2021. Univariate analysis and multivariable Cox regression models were used to examine the factors associated with early (&amp;lt; 5 years since diagnosis) and late (≥ 5 years since diagnosis) recurrence. Results: The median age of diagnosis was 57 (± 10) years, with 35% diagnosed before menopause. While 64% of patients self-reported as White, 16% identified as Asian, 6% Black, 12% Hispanic, and 2% other ethnicity. After a median 13.3 (range: 0.6-16.8) years of follow up, a total of 341 (13.8%) recurrences occurred, with 158 before and 181 at or after 5 years from diagnosis. Approximately a third of recurrences were local or regional and the other two thirds were distant. In univariate analysis, increasing stage and tumor grade were associated with higher risk of both early and late recurrence (p&amp;lt; 0.05). Progesterone receptor (PR) negativity was associated with only early (hazard ratio [HR]=1.49, 95% confidence interval [CI] 1.06-2.09) but not late recurrence (HR=0.90, 95% CI 0.63-1.28). In unadjusted models, receiving lumpectomy (vs. mastectomy), chemotherapy, radiation therapy, or endocrine therapy were associated with lower risk of both early and late recurrence. Among the demographic and lifestyle factors examined, postmenopausal status at diagnosis was associated with lower risk of early (HR=0.69, 95% CI 0.51-0.96) but not late recurrence (HR=1.00, 95% CI 0.73-1.36). No association was found with body mass index, socioeconomic measures (education, income, employment, marital status), smoking, alcohol intake, or physical activity assessed at the time close to diagnosis. Notably, minoritized racial/ethnic groups all had higher risk of early recurrence than White women (Asian: HR=1.76, 95% CI 1.16-2.66; Black: HR=2.33, 95% CI 1.38-3.93; Hispanic: HR=1.80, 95% CI 1.15-2.82), but no association was found with late recurrence (Asian: HR=0.99, 95% CI 0.65-1.51; Black: HR=0.80, 95% CI 0.41-1.58; Hispanic: HR=0.80, 95% CI 0.48-1.33). In multivariable Cox models adjusted for age, cancer stage, grade, PR status, surgery, radiation therapy, chemotherapy, and endocrine therapy, the trend of higher risk of early recurrence among minoritized racial/ethnic groups remained, although the association remained significant only in Black women (HR=1.89, 95% CI 1.08-3.31). Conclusion: Most histopathological features and cancer treatment modality had similar impact on early vs. late recurrence among women with early-stage ER-positive breast cancer, although PR negativity might be an adverse risk factor for early recurrence only. The findings of higher risk of early but not late recurrence among Asian, Black, and Hispanic relative to White women provide some novel data on the racial/ethnic disparities of prognosis for ER-positive breast cancer and may warrant further investigation. Citation Format: Alfredo Chua, Haiyang Sheng, Shipra Gandhi, Marilyn Kwan, Isaac Ergas, Janise Roh, Cecile Laurant, Thaer Khoury, Scarlett Gomez, Christine Ambrosone, Lawrence Kushi, Song Yao. Demographic, Lifestyle, and Clinical Factors Associated with Early vs. Late Recurrence among Women with Early-Stage Estrogen Receptor-Positive Breast Cancer in the Prospective Pathways Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-11.

Abstract PO3-07-07: Predictive Modeling for Identifying Breast Cancer Patients Eligible for Axillary Lymph Node Dissection Exemption Following Neoadjuvant Therapy: A Longitudinal MRI-based Radiomics and Deep Learning Features Analysis

Abstract Objective: Neoadjuvant therapy (NAC) has emerged as a pivotal treatment modality for breast cancer. However, accurately identifying patients who can safely avoid axillary lymph node dissection (ALND) following NAC remains challenging. In this study, our aim was to develop a predictive model using longitudinal MRI-based radiomics and deep learning features to identify breast cancer patients suitable for exemption from ALND. Methods: A total of 140 patients with cN1-2 breast cancer who underwent NAC were included in this study between January 2021 and October 2022. MRI images were collected before and after two cycles of NAC. The dataset was randomly divided into training and validation sets using a 7:3 ratio. Logistic regression (LR), K-nearest neighbors (KNN), LightGBM, and multilayer perceptron (MLP) machine learning models were utilized to predict axillary lymph node pathological complete response (ypN0) in patients following NAC. Finally, a prediction model with a single modality feature was trained by integrating all the extracted data. Results: Among the 140 patients included, 55 achieved ypN0 following NAC, while 85 did not achieve ypN0. Modeling the features extracted from pre- and post-chemotherapy evaluations revealed that the LR model achieved the highest area under the curve (AUC) values, reaching 0.842 and 0.841, respectively. Moreover, by integrating the evaluation of pre- and post-chemotherapy images and the net change of features between the two time points, the novel developed Amalgamation model demonstrated the highest AUC value of 0.958. The Amalgamation model exhibited an accuracy of 0.9, sensitivity of 0.833, and specificity of 1. Conclusion: Our study developed a predictive model using MRI images obtained before and after two cycles of NAC to identify breast cancer patients with ypN0 at an early stage. This model has the potential to avoid unnecessary ALND, significantly reducing complications. Keywords: breast cancer, neoadjuvant chemotherapy, axillary lymph node dissection, MRI, radiomics, deep learning, predictive modeling Figure 1: The ROC curves of Amalgamation model, Delta-model, Two-cycle reassessment-model and Baseline-model based on Logistic regression. Table 1: Performances of combining different machine learning models for predicting axillary lymph node pathological complete response to neoadjuvant therapy in pre- and post-neoadjuvant therapy MRI images. Citation Format: Yushuai Yu, Jialu Yi, Ruiliang Chen, Kaiyan Huang, Jie Zhang, Chuangui Song. Predictive Modeling for Identifying Breast Cancer Patients Eligible for Axillary Lymph Node Dissection Exemption Following Neoadjuvant Therapy: A Longitudinal MRI-based Radiomics and Deep Learning Features Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-07-07.

Abstract PO5-24-12: IRX5010, a Highly Selective RARγ Nuclear Receptor Agonist Compound Inhibits In Vivo Growth of Murine EMT-6 Triple Negative Breast Cancer and Human JIMT-1Her2+ Breast Cancer By Induction of Tumor-Infiltrating Effector Memory T-cells

Abstract Research Objectives and Rationale: Previously, RARγ agonism has been shown to play an essential role in CD8 T-cell-mediated immunity to infectious pathogens. However, we found no previous reports on effects of RARγ agonists on in vivo tumor growth of triple negative or Her2+ breast cancers. Here we explored whether RARγ could play a critical role in T-cell-mediated immunity in these breast cancers, using potent highly selective novel RARγ agonist compounds. Experimental methods and results: We synthesized and screened compounds for selective transactivation of RAR γ in reporter assays. Three highly potent compounds, demonstrating highly selective RARγ transactivation at less than one nanomolar concentrations, were selected for further evaluation of potential anti-cancer activities in vitro. None of the three evaluated compounds demonstrated significant inhibitory effects on in vitro growth of EMT-6 triple negative breast cancer cells at concentrations of 20-100 millimolar, indicating that the three compounds have insignificant direct inhibitory effects on EMT-6 cancer cell growth in vitro. We then examined the effects of one of the compounds in vivo in a syngeneic mouse model of EMT-6 triple negative breast cancer. Treatment with the most potent of the three compounds, IRX5010, demonstrated dose response inhibition of in vivo growth of EMT-6 tumors. Inhibition of tumor growth at day 17 relative to vehicle was 59% and 69% respectively in mice treated with IRX5010 at 10 or 25 mg/kg/day. A cohort treated with 50 mg/kg/day was sacrificed early on day 12 due to excessive weight loss and deaths of some of the animals. This cohort experienced a 73% inhibition of tumor growth relative to vehicle. Gross necropsies of animals in the 25 and 50 mg/kg/day dose groups did not show observable pathologic findings in any major organ. Flow cytometry was performed on freshly excised tumors on the day of termination of the in-life portion of the study in the 10 and 25 mg/kg/day dose groups. Tumors from mice treated with IRX5010 had increased intratumoral numbers of Total CD45+ cells; Total CD3+, Total CD4+, and Total CD8+ T-cells per mg of tumor tissue, relative to vehicle controls. IRX5010 treated mice also had increased intratumoral CD4+IL-17+ T-helper cells; and increased CD4+CD62L- and CD8+CD62L- T-effector memory T-cells per mg of tumor tissue relative to vehicle-treated control mice. We also conducted an experiment of treatment with IRX5010 in mice transplanted with human immune cells (to provide a human immune system) to examine its effects on xenografted human Her2+ JIMT-1 cancer cells. In this model, treatment with IRX5010 at 10 mg/kg/day resulted in a 17% inhibition of tumor growth relative to vehicle control over 26 days of treatment. Flow cytometric analysis showed that tumors from the IRX5010 treated mice contained increased numbers per mg of tumor tissue of intratumoral human CD8+ T-cells, most of which were CD8+ CD7- CD45RA+ terminally differentiated effector memory phenotype T-cells. Conclusions: Treatment with IRX5010, a potent and highly selective RARγ nuclear receptor agonist compound demonstrated substantial treatment effects relative to vehicle control on inhibition of growth of murine triple negative breast cancer in vivo, despite having essentially no growth inhibitory effect on these cells in vitro. Treatment of xenografted human Her2+ tumors in mice with humanized immune systems resulted in a moderate inhibition of Her2+ breast cancer growth relative to vehicle controls. In both models, treatment with IRX5010 induced tumor infiltrating T-lymphocytes of largely effector memory phenotypes, demonstrating an effect on the tumor immune microenvironment. These data identify RARγ and RARγ agonists as a new treatment target and novel treatment modality for breast cancers, especially for the highly unmet need for new and better treatments for triple negative breast cancer. Citation Format: Martin Sanders, Mary Topalovski, Vidyasagar Vuligonda. IRX5010, a Highly Selective RARγ Nuclear Receptor Agonist Compound Inhibits In Vivo Growth of Murine EMT-6 Triple Negative Breast Cancer and Human JIMT-1Her2+ Breast Cancer By Induction of Tumor-Infiltrating Effector Memory T-cells [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-24-12.

Beta cyclodextrin conjugated Au[sbnd]Fe3O4 Janus nanoparticles with enhanced chemo-photothermal therapy performance

The strategic integration of multi-functionalities within a singular nanoplatform has received growing attention for enhancing treatment efficacy, particularly in chemo-photothermal therapy. This study introduces a comprehensive concept of Janus nanoparticles (JNPs) composed of Au and Fe3O4 nanostructures intricately bonded with β-cyclodextrins (β-CD) to encapsulate 5-Fluorouracil (5-FU) and Ibuprofen (IBU). This strategic structure is engineered to exploit the synergistic effects of chemo-photothermal therapy, underscored by their exceptional biocompatibility and photothermal conversion efficiency (∼32.88 %). Furthermore, these β-CD-conjugated JNPs enhance photodynamic therapy by generating singlet oxygen (1O2) species, offering a multi-modality approach to cancer eradication. Computer simulation results were in good agreement with in vitro and in vivo assays. Through these studies, we were able to prove the improved tumor ablation ability of the drug-loaded β-CD-conjugated JNPs, without inducing adverse effects in tumor-bearing nude mice. The findings underscore a formidable tumor ablation potency of β-CD-conjugated Au-Fe3O4 JNPs, heralding a new era in achieving nuanced, highly effective, and side-effect-free cancer treatment modalities. Statement of significanceThe emergence of multifunctional nanoparticles marks a pivotal stride in cancer therapy research. This investigation unveils Janus nanoparticles (JNPs) amalgamating gold (Au), iron oxide (Fe3O4), and β-cyclodextrins (β-CD), encapsulating 5-Fluorouracil (5-FU) and Ibuprofen (IBU) for synergistic chemo-photothermal therapy. Demonstrating both biocompatibility and potent photothermal properties (∼32.88 %), these JNPs present a promising avenue for cancer treatment. Noteworthy is their heightened photodynamic efficiency and remarkable tumor ablation capabilities observed in vitro and in vivo, devoid of adverse effects. Furthermore, computational simulations validate their interactions with cancer cells, bolstering their utility as an emerging therapeutic modality. This endeavor pioneers a secure and efficacious strategy for cancer therapy, underscoring the significance of β-CD-conjugated Au-Fe3O4 JNPs as innovative nanoplatforms with profound implications for the advancement of cancer therapy.

Comprehensive studies on the biological activities of human metastatic (MDA-MB-231) and non-metastatic (MCF-7) breast cancer cell lines, directly or combinedly treated using non-thermal plasma-based approaches

Progressive incidence and a pessimistic survival rate of breast cancer in women worldwide remains one of the most concerning topics. Progressing research indicates a potentially high effectiveness of use cold atmospheric plasma (CAP) systems. The undoubted advantage seems its simplicity in combination with other anti-cancer modalities. Following observed trend of studies, one inventory CAP system was applied to directly treat human breast cancer cell lines and culturing in two different Plasma Activated Media (PAM) for combined utilization. Proposed CAP treatments on MCF-10 A, MCF-7, and MDA-MB-231 cell lines were studied in terms of impact on cell viability by MTT assay. Disturbances in cell motility following direct and combined CAP application were assessed by scratch test. Finally, the induction of apoptosis and necrosis was verified with annexin V and propidium iodide staining. Reactive species generated during CAP treatment were determined based on optical emission spectrometry analysis along with colorimetric methods to qualitatively assess the NO2−, NO3−, H2O2, and total ROS with free radicals concentration. The most effective approach for CAP utilization was combined treatment, leading to significant disruption in cell viability, motility and mostly apoptosis induction in breast cancer cell lines. Determined CAP dose allows for mild outcome, showing insignificant harm for the non-cancerous MCF-10 A cell line, while the highly aggressive MDA-MB-231 cell line shows the highest sensitivity on proposed CAP treatment. Direct CAP treatment seems to drive the cells into the sensitive state in which the effectiveness of PAM is boosted. Observed anti-cancer response of CAP treatment was mostly triggered by RNS (mostly NO2− ions) and ROS along with free radicals (such as H2O2, OH•, O2-•, 1O2, HO2•). The combined application of one CAP source represent a promising alternative in the development of new and effective modalities for breast cancer treatment.

Acid-Activated TAT Peptide-Modified Biomimetic Boron Nitride Nanoparticles for Enhanced Targeted Codelivery of Doxorubicin and Indocyanine Green: A Synergistic Cancer Photothermal and Chemotherapeutic Approach.

The evolution of nano-drug delivery systems addresses the limitations of conventional cancer treatments with stimulus-responsive nanomaterial-based delivery systems presenting temporal and spatial advantages. Among various nanomaterials, boron nitride nanoparticles (BNNs) demonstrate significant potential in drug delivery and cancer treatment, providing a high drug loading capacity, multifunctionality, and low toxicity. However, the challenge lies in augmenting nanomaterial accumulation exclusively within tumors while preserving healthy tissues. To address this, we introduce a novel approach involving cancer cell membrane-functionalized BNNs (CM-BIDdT) for the codelivery of doxorubicin (Dox) and indocyanine green to treat homologous tumor. The cancer cell membrane biomimetic CM-BIDdT nanoparticles possess highly efficient homologous targeting capabilities toward tumor cells. The surface modification with acylated TAT peptides (dTAT) further enhances the nanoparticle intracellular accumulation. Consequently, CM-BIDdT nanoparticles, responsive to the acidic tumor microenvironment, hydrolyze amide bonds, activate the transmembrane penetrating function, and achieve precise targeting with substantial accumulation at the tumor site. Additionally, the photothermal effect of CM-BIDdT under laser irradiation not only kills cells through thermal ablation but also destroys the membrane on the surface of the nanoparticles, facilitating Dox release. Therefore, the fabricated CM-BIDdT nanoparticles orchestrate chemo-photothermal combination therapy and effectively inhibit tumor growth with minimal adverse effects, holding promise as a new modality for synergistic cancer treatment.

Self-assembled IR dye/Mitoxantrone loaded Porphysomes Nanosystem for Enhanced Combinatorial Chemo-Photothermal Cancer Therapy

Chemo-photothermal therapy (PTT) is an emerging non-invasive cancer treatment modality. Light-responsive porphysomes (DPP IR Mtx @Lipo NPs) nanosystems ablate breast cancer cells upon oxidative stress and hyperthermia. The unique self-assembled porphysomes were formed spherical shape in the size range of 150 ± 30nm formed by the co-assembly of porphyrins along with IR 775 and chemotherapeutic drug, Mitoxantrone (Mtx), forming a camouflaged nanosystem (DPP IR Mtx @Lipo NPs, porphysomes). The advent of the prepared porphysomes aids in proper tuning of NIR absorbance improving singlet oxygen species generation among other anticancer drugs. The eminent release of DPP and adjuvant chemo-drug, Mitoxantrone from the self-assembled porphysomes is triggered by IR 775, a NIR photosensitizer upon laser irradiation. These multifunctional DPP IR Mtx @Lipo NPs have an efficient photothermal conversion efficiency of 65.8% as well as bioimaging properties. In-vitro studies in 2D and 3D models showed a significant cell death of 4T1 cells via the apoptotic pathway when irradiated with NIR laser, causing minimal damage to nearby healthy cells. DPP IR Mtx @Lipo NPs exhibited commingled PDT/PTT interdependent via NIR laser exposure, leading to mitochondrial disruption. Interestingly, the transient transfection using p53-GFP in cancer cells followed by DPP IR Mtx @Lipo NPs treatment causes rapid cell death. The activation of p53-dependent apoptosis pathways was vividly expressed, evidenced by the upregulation of Bax and increased pattern of Caspase-3 cleavage. This effect was pronounced upon transfection and induction with DPP IR Mtx @Lipo NPs, particularly in comparison to non-transfected malignant breast cancer 4T1 cells.

Water-Soluble Small Organic Fluorophores for Oncological Theragnostic Applications: Progress and Development.

Cancer is one of the major noncommunicable diseases, responsible for millions of deaths every year worldwide. Though various cancer detection and treatment modalities are available today, many deaths occur owing to its late-stage detection and metastatic nature. Noninvasive detection using luminescence-based imaging tools is considered one of the promising techniques owing to its low cost, high sensitivity, and brightness. Moreover, these tools are unique and valuable as they can detect even the slightest changes in the cellular microenvironment. To achieve this, a fluorescent probe with strong tumor uptake and high spatial and temporal resolution, especially with highwatersolubility, is highly demanded. Recently, several water-soluble molecules with emission windows in the visible (400-700nm), first near-infrared (NIR-I, 700-1000nm), and second near-infrared (NIR-II, 1000-1700nm) windows have been reported in literature. This review highlights recently reported water-soluble small organic fluorophores/dyes with applications in cancer diagnosis and therapeutics. We systematically highlight and describe the key concepts, structural classes of fluorophores, strategies for imparting water solubility, and applications in cancer therapy and diagnosis, i.e., theragnostics. We discuss examples of water-soluble fluorescent probes based on coumarin, xanthene, boron-dipyrromethene (BODIPY), and cyanine cores. Some other emerging classes of dyes based on carbocyclic and heterocyclic cores are also discussed. Besides, emerging molecular engineering methods to obtain such fluorophores are discussed. Finally, the opportunities and challenges in this research area are also delineated.