Normal Tissue Effects Research Articles

Photobiomodulation preconditioning for oral mucositis prevention and quality of life improvement in chemotherapy patients: a randomized clinical trial

BackgroundGiven the suffering experienced by cancer patients, effective solutions must be found to prevent painful and debilitating side effects of anti-cancer treatment. This trial aims to study the effect of preconditioning with photobiomodulation in preventing oral mucositis and xerostomia in cancer patients undergoing chemotherapy alone for the first time, and to examine its role in improving patients’ quality of life.Materials and methodsThis is a prospective, randomized, double-blind clinical trial including 45 patients divided into three age- and sex-matched groups. Group 1 received basic oral care instructions before undergoing chemotherapy. Group 2 received basic oral care instructions plus photobiomodulation using an intraoral 650 nm diode laser. Group 3 received basic oral care instructions plus photobiomodulation using a 650 nm diode laser intraorally and a 980 nm diode laser extraorally.ResultsAfter one week of follow-up, 73.3% of patients in Group 2 and 80% in Group 3 did not develop oral mucositis. The remaining patients in both groups experienced only mild erythema. In contrast, all patients in Group 1 developed oral mucositis, ranging from mild erythema to ulceration greater than 3 cm². After two weeks of follow-up, 80% of patients in Group 2 and 86.7% in Group 3 remained free of oral mucositis. The remaining patients in both groups experienced only mild erythema. In contrast, 93.3% of patients in Group 1 developed oral mucositis, with cases ranging from mild erythema to ulcers larger than 3 cm². There were statistically significant differences between the three groups in oral mucositis assessment scale after one week and after two weeks (p < 0.001). Specifically, ulcerative mucositis was not observed in both laser groups, while it was observed in 13.3% of patients in Group 1. However, these differences were not statistically significant (p = 0.129). Regarding Late Effects in Normal Tissue (LENT-SOMA) scale, there was a statistically significant difference between the three groups studied (p = 0.037). There was also a statistically significant difference in the Oral Health Impact Profile (OHIP-14) between the three groups studied (p = 0.003 after one week, p = 0.023 after two weeks).ConclusionPreconditioning before starting chemotherapy, whether with the intraoral red laser alone or in combination with the extraoral infrared laser, has shown significant results in preventing oral mucositis and dry mouth, and it has also played a major role in improving patients’ quality of life.Trial registrationThis trial was registered in ISRCTN registry under no ISRCTN70634383 (https://doi.org/10.1186/ISRCTN70634383) on 24/07/2023.

Amplification of Higher-Order Salivary Gland Volume Effects from External Beam Radiotherapy in Normal Tissue Complication Probability Modeling of Radiopharmaceutical Therapy

Salivary glands are common organs at risk in both head and neck external beam radiotherapy (EBRT) and radiopharmaceutical therapy (RPT), but incidences of xerostomia in RPT are inconsistent with the EBRT Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) limits. In EBRT, salivary glands are usually assumed to be parallel organs, with QUANTEC guidelines based on Dmean, but this is known to be a gross over-simplification of the full complexity of the underlying functional organization. The goal of this work is to combine machine learning of EBRT dose–outcome data with stylized small-scale RPT dosimetry to discover more reliable normal tissue complication probability (NTCP) models of xerostomia across both modalities. A retrospective cohort of 211 EBRT patients was analyzed using a custom-designed in-house machine learning workflow. From this, a hierarchy of three models of increasing complexity was trained, evaluated for performance and generalization, and coupled with stylized small-scale salivary gland dosimetry to assess the influence of model complexity on the predicted NTCP for plausible patterns of RPT dose nonuniformity. The three models in the hierarchy (A, B, C), in increasing order of complexity, associate xerostomia with the following: the mean dose to the whole contralateral parotid (model A), the mean dose to a ductally localized region (model B) and a serial interaction dose term between two ductal sub-compartments (model C). While the difference between the three models for EBRT p-values and AUCs is rather marginal, for physiologically driven ductal dose distributions in RPT, the predicted reduction in TD50 can be as large as a factor of 10. These results provide hints towards a plausible reconciliation of the observed inconsistency of xerostomia in RPT with EBRT dose limits.

A prodrug nanodevice co-delivering docetaxel and ROR1 siRNA for enhanced triple negative breast cancer therapy.

Triple-negative breast cancer (TNBC) has been a clinical challenge due to its high recurrence and metastasis rates. Chemotherapy remains the primary treatment for TNBC after surgery ablation, but it lacks targeted specificity and causes side effects in normal tissues. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is significantly expressed in TNBC cells, and small interference RNA (siRNA) targeting ROR1 can effectively suppress ROR1 gene expression, thereby inhibiting proliferation and metastasis. However, clinical application of ROR1 siRNA is limited by susceptibility to clearance and difficulty in endosomal escape. In this study, the docetaxel (DTX) prodrug nanoparticle BBRM delivering ROR1 siRNA was constructed. The BBRM could be effectively internalized by tumor cells and endosomal escape to release DTX and ROR1 siRNA. In 4T1 tumor-bearing mice, BBRM could be targeting delivered to tumor and lung tissues, with good biosafety, achieving a tumor inhibition rate of 74.1 % and inhibiting lung metastasis. By integrating chemotherapy and RNA interference therapy, BBRM successfully co-delivered chemotherapeutic agents and siRNA to improve the therapeutic efficacy of triple-negative breast cancer and provided a promising strategy for clinical transformation. STATEMENT OF SIGNIFICANCE: Chemotherapy is still the primary treatment for triple-negative breast cancer (TNBC) after surgery ablation, but it causes side effects without targeting capacity. ROR1 is significantly expressed in TNBC cells, and RNA interference for ROR1 can suppress ROR1 gene expression to inhibit tumor proliferation. However, as oligonucleotides, effect of ROR1 siRNA is limited by susceptibility to clearance and difficulty in endosomal escape. In this work, we designed a nanodevice based on a docetaxel (DTX) prodrug that targets ROR1 for the synergistic therapy of TNBC. We constructed a nanoparticle (BBRM) for co-delivery of the DTX and ROR1 siRNA. The BBRM could be effectively internalized by tumor cells and endosomal escape. The ROR1 siRNA downregulated ROR1 protein expression and improved the anti-proliferative and anti-metastatic effects. In addition, BBRM reversed the immunosuppressive tumor microenvironment, thus improving breast cancer therapeutic efficacy. It was a pioneering investigation in synergistic chemo-gene therapy by co-delivering DTX and ROR1 siRNA for TNBC treatment.

Hypofractionated partial breast irradiation after breast-conserving surgery for patients with early stage breast cancer in China Mainland: a single-arm prospective trial

To report the results of a single-arm, prospective partial breast irradiation (PBI) trial from China mainland using a dose of 40.05 Gy in 15 fractions delivered with intensity-modulated radiation therapy (IMRT) technique for patients with early stage breast cancer. Patients aged ≥ 50 years who underwent breast-conserving surgery for unifocal non-lobular invasive breast cancer, with pathological T1 disease, clear margins, negative axillary nodes, and positive hormonal receptors, were recruited. The primary endpoint was 3-year cosmetic deterioration, and secondary endpoints included adverse events, ipsilateral breast tumor recurrence (IBTR), regional recurrence, and survivals. This trial is registered with ClinicalTrials.gov (registration No. NCT03411174). From Jan of 2015 to July of 2018, 208 out of 222 patients recruited were evaluable and included in final analysis. The median follow-up was 66.3 (range: 42.0-105.4) months. The 3-year overall cosmetic deterioration rate was 3.5%. The rates of grade 2 radiation dermatitis and breast induration was 5.8% and 1.5%, respectively. No one experienced ≥ grade 2 breast pain, edema, or telangiectasia. The 5-year cumulative incidence of IBTR and RR was 0.5%. No one developed DM. The 5-year DFS was 99.0%. Four patients died from non-breast cancer causes, and the 5- year OS was 97.9%. In conclusion, we observed lower rates of cosmetic deterioration, IBTR, and ≥ grade 2 acute/late normal tissue effects following PBI with a moderately hypofractionated regimen delivered with IMRT technique. Therefore, this regimen represents an attractive option when an external beam PBI approach is chosen to treat a patient with low-risk early breast cancer.

Prodrug-based bispecific antibodies for cancer therapy: advances and future directions.

Bispecific antibodies represent an innovative paradigm in cancer therapy, offering broader therapeutic potential compared to conventional monoclonal antibodies. To increase tumor selectivity while mitigating off-target effects in normal tissues, the concept of prodrug-based bispecific antibodies has emerged. This review delineates the various mechanisms underlying the action of prodrug-based bispecific antibodies, including protease-mediated activation, steric hindrance release via proteolytic processing, activation by soluble factors, conditional assembly, and chain exchange-mediated activation. We also address the critical challenges that must be overcome to optimize the development and clinical application of these sophisticated therapeutic agents.

Integrating A Role of Injectable Hydrogel for Localized Cancer Therapy

Traditional intravenous chemotherapy is often associated with adverse effects in normal cells and tissues including liver or kidney dysfunction and neurotoxicity, myelosupression. As an alternative approach Localized chemotherapy can minimise the toxicity and side effects. As an alternative method, the injectable hydrogel can effectively reduce this type of adverse effects by releasing drugs topically at the tumor site . Based on the different types of stages of Cancer a number of Hydrogel based drug delivery have been developed that is thermo sensitive ,pH sensitive, photo sensitive and dual sensitive hydrogel. The recent advancement in this hydrogels and related drug discovery mostly injectable hydrogel for localised cancer therapy is used more effectively than traditional chemotherapy. This therapy is briefly discussed in this article.

Molecular mechanisms of mTOR-mediated cisplatin response in tumor cells.

Cisplatin (CDDP) is one of the main chemotherapeutic drugs that is widely used in many cancers. However, CDDP resistance is a frequent therapeutic challenge that reduces prognosis in cancer patients. Since, CDDP has noticeable side effects in normal tissues and organs, it is necessary to assess the molecular mechanisms associated with CDDP resistance to improve the therapeutic methods in cancer patients. Drug efflux, detoxifying systems, DNA repair mechanisms, and drug-induced apoptosis are involved in multidrug resistance in CDDP-resistant tumor cells. Mammalian target of rapamycin (mTOR), as a serine/threonine kinase has a pivotal role in various cellular mechanisms such as autophagy, metabolism, drug efflux, and cell proliferation. Although, mTOR is mainly activated by PI3K/AKT pathway, it can also be regulated by many other signaling pathways. PI3K/Akt/mTOR axis functions as a key modulator of drug resistance and unfavorable prognosis in different cancers. Regarding, the pivotal role of mTOR in CDDP response, in the present review we discussed the molecular mechanisms that regulate mTOR mediated CDDP response in tumor cells.

Thyroid avoidance in treatment planning for breast cancer patients irradiated to the supraclavicular nodes.

Hypothyroidism affects up to 21% of women with breast cancer after supraclavicular node irradiation. The PENTEC (pediatric normal tissue effects in the clinic) initiative highlighted the need to minimize the thyroid dose, albeit without giving aspecific constraint. This study aimed to define areasonable target thyroid mean dose (Dmean) between 10 and 15 Gy using intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) and examine its impact on the hypothyroidism risk. Forty-three breast cancer patients with supraclavicular irradiation neglecting the thyroid in terms of dose protection were included from 01/2020 to 04/2021. An IMRT or VMAT technique was used in23 and 20patients, respectively. Replanning aimed for athyroid Dmean of 10 Gy. IMRT plans still exceeding 10 Gy were converted into VMAT plans. Fisher's sign test compared original and revised plans and the hypothyroidism risk was calculated. Initial radiotherapy plans had athyroid Dmean of 18.4 ± 7.9 Gy (IMRT: 20.4 ± 8.8 Gy, VMAT: 16.2 ± 6.2 Gy). Replanning significantly reduced Dmean to 10.3 ± 4.5 Gy (-44%) overall (IMRT: -50%, VMAT: -35%), with 56% achieving ≤ 10 Gy (IMRT: 33.3%, VMAT: 61%). Furthermore, an IMRT to VMAT conversion yielded athyroid Dmean of 9.2 ± 3.5 Gy, with 74.4% of patients ≤ 10 Gy, albeit at the cost of higher doses to the contralateral breast. Clinical and planning target volume (CTV/PTV) coverage remained uncompromised. The calculated hypothyroidism risk significantly decreased from 24.5% to 13.3% (Dmean = 10 Gy) or 16.3% (Dmean = 13.5 Gy). Implementing athyroid organ at risk (OAR) constraint Dmean of 13.5 Gy was feasible in 88% of patients without compromising other OARs and CTV/PTV coverage, and resulted in a33-46% reduction of the hypothyroidism risk. Retrospectively registered.

Tumor Receptor-Mediated Morphological Transformation and In Situ Polymerization of Diacetylene-Containing Lipidated Peptide Amphiphile on Cell Membranes for Tumor Suppression.

In situ polymerization on cell membranes can decrease cell mobility, which may inhibit tumor growth and invasion. However, the initiation of radical polymerization traditionally requires exogenous catalysts or free radical initiators, which might cause side effects in normal tissues. Herein, we synthesized a Y-type diacetylene-containing lipidated peptide amphiphile (TCDA-KFFFFK(GRGDS)-YIGSR, Y-DLPA) targeting integrins and laminin receptors on murine mammary carcinoma 4T1 cells, which underwent nanoparticle-to-nanofiber morphological transformation and in situ polymerization on cell membranes. Specifically, the polymerized Y-DLPA induced 4T1 cell apoptosis and disturbed the substance exchange and metabolism. In vitro assays demonstrated that the polymerized Y-DLPA nanofibers decreased the migration capacity of 4T1 cells, potentially suppressing tumor invasion and metastasis. When administered locally to 4T1 tumor-bearing mice, the Y-DLPA nanoparticles formed a biomimetic extracellular matrix that effectively suppressed tumor growth. This study provides an in situ polymerization strategy that can serve as an effective drug-free biomaterial with low side effects for antitumor therapy.

Selective Cytotoxicity and Gene Expression Profiles in Response to Methanolic Extract of Phyllanthus amarus Extract against MCF-7 Breast Cancer Cells

Background Breast cancer, a malignant tumor, is the most common cancer type among women worldwide. Conventional chemotherapy treatments for breast cancer often cause adverse side effects in normal tissues and can lead to treatment failure. Plant-derived natural compounds offer an effective alternative with fewer side effects for cancer patients. Phyllanthus amarus is a medicinal plant widely distributed in China, India, and Brazil and reported to be used for the treatment of various types of cancer. Purpose This study was aimed to investigate the anticancer efficacy of methanolic extract of P. amarus against MCF-7 breast cancer cells. Methods We probed the anticancer activity in MCF-7 breast cancer cells by isolating the methanolic extract of P. amarus leaf extract (MEPA). The standard chemotherapy drug docetaxel is combined with MEPA to increase the drug efficacy. Moreover, the intracellular reactive oxygen species (ROS), alterations in mitochondrial membrane potential (MMP), nuclear condensation, and apoptotic activation were investigated in MCF-7 cells. Additionally, the customized PCR array comprising of cell cycle, apoptosis, mTOR, and JAK-STAT-related genes was studied during different MEPA treatments. Results In the MCF-7 breast cancer cells, the MEPA and docetaxel combination demonstrated strong cytotoxicity, with IC50 values of 45 and 2.6 µg/mL, respectively. MEPA and docetaxel together exhibited enhanced alterations in MMP and increased generation of ROS in MCF-7 cells. Furthermore, the combination of docetaxel with MEPA induces nuclear condensation and apoptotic cell death. During MEPA treatment, the gene expression profiles in MCF-7 cells were accessed. The JAK-STAT, mTOR signaling pathway, apoptosis, and cell growth-related genes were strongly affected by the dose-dependent administration of MEPA. Conclusion This study suggests that MEPA could be a useful alternative treatment for breast cancer. When combined with traditional chemotherapy, MEPA might offer better results with fewer side effects. More in vivo studies are needed to confirm MEPA’s effectiveness in animal models.

The Metformin Immunoregulatory Actions in Tumor Suppression and Normal Tissues Protection.

The immune system is the key player in a wide range of responses in normal tissues and tumors to anticancer therapy. Inflammatory and fibrotic responses in normal tissues are the main limitations of chemotherapy, radiotherapy, and also some newer anticancer drugs such as immune checkpoint inhibitors (ICIs). Immune system responses within solid tumors including anti-tumor and tumor-promoting responses can suppress or help tumor growth. Thus, modulation of immune cells and their secretions such as cytokines, growth factors and epigenetic modulators, pro-apoptosis molecules, and some other molecules can be suggested to alleviate side effects in normal tissues and drug-resistance mechanisms in the tumor. Metformin as an anti-diabetes drug has shown intriguing properties such as anti-inflammation, anti-fibrosis, and anticancer effects. Some investigations have uncovered that metformin can ameliorate radiation/chemotherapy toxicity in normal cells and tissues through the modulation of several targets in cells and tissues. These effects of metformin may ameliorate severe inflammatory responses and fibrosis after exposure to ionizing radiation or following treatment with highly toxic chemotherapy drugs. Metformin can suppress the activity of immunosuppressive cells in the tumor through the phosphorylation of AMP-activated protein kinase (AMPK). In addition, metformin may stimulate antigen presentation and maturation of anticancer immune cells, which lead to the induction of anticancer immunity in the tumor. This review aims to explain the detailed mechanisms of normal tissue sparing and tumor suppression during cancer therapy using adjuvant metformin with an emphasis on immune system responses.

Tumor Microenvironment Activated Cu Crosslinked Near-Infrared Sonosensitizers for Visualized Cuproptosis-Enhanced Sonodynamic Cancer Immunotherapy.

Reactive oxygen species (ROS)-mediated sonodynamic therapy (SDT) holds increasing potential in treating deep-seated tumor owing to the high tissue-penetration depth. However, the inevitable accumulation of sonosensitizers in normal tissues not only make it difficult to realize the in situ SDT, but also induces sonodynamic effects in normal tissues. Herein, this work reports the passivation and selective activation strategies for the sonodynamic and near-infrared (NIR) imaging performances of an intelligent antitumor theranostic platform termed Cu-IR783 nanoparticles (NPs). Owing to the ruptured coordination bond between IR783 with Cu ions by responding to tumor microenvironment (TME), the selective activation of IR783 only occurred in tumor tissues to achieve the visualized in-situ SDT. The tumor-specific released Cu ions not only realized the cascade amplification of ROS generation through Cu+-mediated Fenton-like reaction, but also triggered cuproptosis through Cu+-induced DLAT oligomerization and mitochondrial dysfunction. More importantly, the immunosuppressive TME can be reversed by the greatly enhanced ROS levels and high-efficiency cuproptosis, ultimately inducing immunogenic cell death that promotes robust systemic immune responses for the eradication of primary tumors and suppression of distant tumors. This work provides a distinct paradigm of the integration of SDT, CDT, and cuproptosis in a controlled manner to achieve visualized in-situ antitumor therapy.

Efficient Capture and Traceless Release of Functional CD8+ T Cells with a Microfluidic Chip for Enhanced In Vitro and In Vivo CD4-CAR Transduction.

The chimeric antigen receptor (CAR) T cells targeting CD4 expressed cells in acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) could reduce the risk of off target effects in normal tissues. However, the efficacy of adoptive cell therapy is predominantly attributed to CD8+ T cells, necessitating their purification before lentivirus transfection to enhance the production of CD4-CAR-T cells. In this study, we developed a microfluidic chip functionalized with an optimized CD8 aptamer, A3t-MU, to facilitate the enrichment and purification of CD8+ T cells. The presented chip showed efficient capture and seamless release of CD8+ T cells from cultured T cells and peripheral blood mononuclear cells (PBMCs). The purity of the released CD8+ T cells reached 98.1%, representing a 13% improvement over the conventional magnetic bead separation method. CD4-CAR was efficiently transduced into the purified CD8+ T cells to construct CAR-T cells. We evaluated the antitumor capability of the CD4-CAR transduced CD8+ T cells (anti-CD4 CD8-CAR T cells) both in vitro and in vivo. The anti-CD4 CD8-CAR T cells exhibited significant cancer-cell-killing capacity across multiple tumor cell lines, including CEM, Jurkat, and MV4-11. Meanwhile, anti-CD4 CD8-CAR T cells significantly inhibited tumor growth in vivo. In conclusion, the presented microfluidic chip offers a cost-effective and high-purity approach for CD8+ T cell separation, enhancing CD4-CAR transduction and achieving efficient antitumor capability both in vitro and in vivo.

Pressure-enhanced sensing of tissue oxygenation via endogenous porphyrin: Implications for dynamic visualization of cancer in surgery

Fluorescence guidance is routinely used in surgery to enhance perfusion contrast in multiple types of diseases. Pressure-enhanced sensing of tissue oxygenation (PRESTO) via fluorescence is a technique extensively analyzed here, that uses an FDA-approved human precursor molecule, 5-aminolevulinic acid (ALA), to stimulate a unique delayed fluorescence signal that is representative of tissue hypoxia. The ALA precontrast agent is metabolized in most tissues into a red fluorescent molecule, protoporphyrin IX (PpIX), which has both prompt fluorescence, indicative of the concentration, and a delayed fluorescence, that is amplified in low tissue oxygen situations. Applied pressure from palpation induces transient capillary stasis and a resulting transient PRESTO contrast, dominant when there is near hypoxia. This study examined the kinetics and behavior of this effect in both normal and tumor tissues, with a prolonged high PRESTO contrast (contrast to background of 7.3) across 5 tumor models, due to sluggish capillaries and inhibited vasodynamics. This tissue function imaging approach is a fundamentally unique tool for real-time palpation-induced tissue response in vivo, relevant for chronic hypoxia, such as vascular diseases or oncologic surgery.

5-aminolevulinic acid induced photodynamic reactions in diagnosis and therapy for female lower genital tract diseases.

Since the patients suffering from female lower genital tract diseases are getting younger and younger and the human papilloma virus (HPV) infection is becoming more widespread, the novel non-invasive precise modalities of diagnosis and therapy are required to remain structures of the organ and tissue, and fertility as well, by which the less damage to normal tissue and fewer adverse effects are able to be achieved. In all nucleated mammalian cells, 5-Aminolevulinic acid (5-ALA) is an amino acid that occurs spontaneously, which further synthesizes in the heme biosynthetic pathway into protoporphyrin IX (PpIX) as a porphyrin precursor and photosensitizing agent. Exogenous 5-ALA avoids the rate-limiting step in the process, causing PpIX buildup in tumor tissues. This tumor-selective PpIX distribution after 5-ALA application has been used successfully for tumor photodynamic diagnosis (PDD) and photodynamic therapy (PDT). Several ALA-based drugs have been used for ALA-PDD and ALA-PDT in treating many (pre)cancerous diseases, including the female lower genital tract diseases, yet the ALA-induced fluorescent theranostics is needed to be explored further. In this paper, we are going to review the studies of the mechanisms and applications mainly on ALA-mediated photodynamic reactions and its effectiveness in treating female lower genital tract diseases.

Porphyrin-Based Organic Nanoparticles with NIR-IIa Fluorescence for Orthotopic Glioblastoma Theranostics.

The development of efficient theranostic nanoagents for the precise diagnosis and targeted therapy of glioblastoma (GBM) remains a big challenge. Herein, we designed and developed porphyrin-based organic nanoparticles (PNP NPs) with strong emission in the near-infrared IIa window (NIR-IIa) for orthotopic GBM theranostics. PNP NPs possess favorable photoacoustic and photothermal properties, high photostability, and low toxicity. After modification with the RGD peptide, the obtained PNPD NPs exhibited enhanced blood-brain barrier (BBB) penetration capability and GBM targeting ability. NIR-IIa imaging was employed to monitor the in vivo biodistribution and accumulation of the nanoparticles, revealing a significant enhancement in penetration depth and signal-to-noise ratio. Both in vitro and in vivo results demonstrated that PNPD NPs effectively inhibited the proliferation of tumor cells and induced negligible side effects in normal brain tissues. In general, the work presented a kind of brain-targeted porphyrin-based NPs with NIR-IIa fluorescence for orthotopic glioblastoma theranostics, showing promising prospects for clinical translation.

Radiation Dose-Volume-Response Relationships for Adverse Events in Childhood Cancer Survivors: Introduction to the Scientific Issues in PENTEC

At its very core, radiation oncology involves a trade-off between the benefits and risks of exposing tumors and normal tissue to relatively high doses of ionizing radiation. This trade-off is particularly critical in childhood cancer survivors (CCS), in whom both benefits and risks can be hugely consequential due to the long life expectancy if the primary cancer is controlled. Estimating the normal tissue-related risks of a specific radiation therapy plan in an individual patient relies on predictive mathematical modeling of empirical data on adverse events. The Pediatric Normal-Tissue Effects in the Clinic (PENTEC) collaborative network was formed to summarize and, when possible, to synthesize dose-volume-response relationships for a range of adverse events incident in CCS based on the literature. Normal-tissue clinical radiation biology in children is particularly challenging for many reasons: (1) Childhood malignancies are relatively uncommon-constituting approximately 1% of new incident cancers in the United States-and biologically heterogeneous, leading to many small series in the literature and large variability within and between series. This creates challenges in synthesizing data across series. (2) CCS are at an elevated risk for a range of adverse health events that are not specific to radiation therapy. Thus, excess relative or absolute risk compared with a reference population becomes the appropriate metric. (3) Various study designs and quantities to express risk are found in the literature, and these are summarized. (4) Adverse effects in CCS often occur 30, 50, or more years after therapy. This limits the information content of series with even very extended follow-up, and lifetime risk estimates are typically extrapolations that become dependent on the mathematical model used. (5) The long latent period means that retrospective dosimetry is required, as individual computed tomography-based radiation therapy plans gradually became available after 1980. (6) Many individual patient-level factors affect outcomes, including age at exposure, attained age, lifestyle exposures, health behaviors, other treatment modalities, dose, fractionation, and dose distribution. (7) Prospective databases with individual patient-level data and radiation dosimetry are being built and will facilitate advances in dose-volume-response modeling. We discuss these challenges and attempts to overcome them in the setting of PENTEC.

Identification of naphthalimide-derivatives as novel PBD-targeted polo-like kinase 1 inhibitors with efficacy in drug-resistant lung cancer cells

Targeting polo-box domain (PBD) small molecule for polo-like kinase 1 (PLK1) inhibition is a viable alternative to target kinase domain (KD), which could avoid pan-selectivity and dose-limiting toxicity of ATP-competitive inhibitors. However, their efficacy in these settings is still low and inaccessible to clinical requirement. Herein, we utilized a structure-based high-throughput virtual screen to find novel chemical scaffold capable of inhibiting PLK1 via targeting PBD and identified an initial hit molecule compound 1a. Based on the lead compound 1a, a structural optimization approach was carried out and several series of derivatives with naphthalimide structural motif were synthesized. Compound 4Bb was identified as a new potent PLK1 inhibitor with a KD value of 0.29μM. 4Bb could target PLK1 PBD to inhibit PLK1 activity and subsequently suppress the interaction of PLK1 with protein regulator of cytokinesis 1 (PRC1), finally leading to mitotic catastrophe in drug-resistant lung cancer cells. Furthermore, 4Bb could undergo nucleophilic substitution with the thiol group of glutathione (GSH) to disturb the redox homeostasis through exhausting GSH. By regulating cell cycle machinery and increasing cellular oxidative stress, 4Bb exhibited potent cytotoxicity to multiple cancer cells and drug-resistant cancer cells. Subcutaneous and oral administration of 4Bb could effectively inhibit the growth of drug-resistant tumors in vivo, doubling the survival time of tumor bearing mice without side effects in normal tissues. Thus, our study offers an orally-available, structurally-novel PLK1 inhibitor for drug-resistant lung cancer therapy.

Longitudinal brain volumetrics in glioma survivors.

Radiation therapy (RT) is used selectively for patients with low-grade glioma (LGG) given the concerns for potential cognitive effects in survivors, but prior cognitive outcome studies among LGG survivors have had inconsistent findings. Translational studies that characterize changes in brain anatomy and physiology after treatment of LGG may help to both contextualize cognitive findings and improve the overall understanding of radiation effects in normal brain tissue. This study aimed to investigate the hypothesis that patients with LGG who are treated with RT will experience greater brain volume loss than those who do not receive RT. This retrospective longitudinal study included all patients with WHO grade 2 glioma who received posttreatment surveillance MRI at the University of Alabama at Birmingham. Volumetric analysis of contralateral cortical white matter (WM), cortical gray matter (GM), and hippocampus was performed on all posttreatment T1-weighted MRI sequences using the SynthSeg script. The effect of clinical and treatment variables on brain volumes was assessed using two-level hierarchical linear models. The final study cohort consisted of 105 patients with 1974 time points analyzed. The median length of imaging follow-up was 4.6 years (range 0.36-18.9 years), and the median number of time points analyzed per patient was 12 (range 2-40). Resection was performed in 79 (75.2%) patients, RT was administered to 61 (58.1%) patients, and chemotherapy was administered to 66 (62.9%) patients. Age at diagnosis (β = -0.06, p < 0.001) and use of RT (β = -1.12, p = 0.002) were associated with the slope of the contralateral cortical GM volume model (i.e., change in GM over time). Age at diagnosis (β = -0.08, p < 0.001), midline involvement (β = 1.31, p = 0.006), and use of RT (β = -1.45, p = 0.001) were associated with slope of the contralateral cortical WM volume model. Age (β = -0.0027, p = 0.001), tumor resection (β = -0.069, p < 0.001), use of chemotherapy (β = -0.0597, p = 0.003), and use of RT (β = -0.0589, p < 0.001) were associated with the slope of the contralateral hippocampus volume model. This study demonstrated volume loss in contralateral brain structures among LGG survivors, and patients who received RT experienced greater volume loss than those who did not. The results of this study may help to provide context for cognitive outcome research in LGG survivors and inform the design of future strategies to preserve cognition.

Abstract 1870: LCB36, a bi-specific antibody drug conjugate (BsADC) utilizing ConjuAll conjugation technology and proprietary prodrug payload selectively activated in cancer cells for treating B-cell blood cancers expressing CD20 and/or CD22

Abstract Although frontline chemoimmunotherapy elicits responses in many B-Cell malignancy patients, treatment options remain limited, and clinical outcomes are suboptimal for those with relapsed or refractory diseases. Minimal residual disease (MRD) can lead to disease relapse despite achieving complete remission through targeted therapy, and tumor heterogeneity is responsible for MRD and compromises the efficacy of targeted therapy, especially in B-cell malignancies. Antibody-drug conjugates (ADCs) play a crucial role in oncology indications, and bispecific antibodies (BsAbs) represent one of the fastest-growing classes of next generation antibody therapeutics for cancer therapy. Several advantages of targeting dual tumor-associated antigens (TAAs) with BsAbs and bi-specific antibody drug conjugates (BsADCs) have been proposed, including improved efficacy, heightened tumor cell specificity, and reduced side effects in normal tissues. Notably, the ability of BsADCs to bind to cancer cells expressing even just one antigen has prompted further investigation into their efficacy in heterogeneous cancer models. LCB36 is a BsADC composed of a BsAb targeting both clinically validated CD20 and CD22, which are expressed in B-Cell malignancy, and a proprietary DNA cross-linking PBD prodrug that is site-specifically conjugated to the BsAb using ConjuAll technology. We assessed the expression levels of CD20 and CD22 in the cancer cell lines. While most cells expressed both antigens, some populations showed a low expression level of CD20 and a high expression level of CD22, while others exhibited the opposite pattern, suggesting heterogeneous expression of the two antigens within the same cell line. To confirm the heterogeneity of the two antigens in blood cancer patients, we analyzed single-cell sequencing data [GSE132509]. Each patient had CD20 and CD22 double-positive cells along with CD20 or CD22 single-positive cells, suggesting the possibility of relapse due to MRD following CD20 or CD22 single-targeted therapy. LCB36 demonstrated superior efficacy in CD20 and CD22 double-positive cell lines and cell-line derived xenografts (CDXs) models compared to ADCs targeting either CD20 or CD22, while showing comparable efficacy to single-target ADCs in CD20 or CD22 single-positive cancer cell lines and CDXs. Pharmacokinetic and toxicokinetic studies of LCB36 were analyzed in rats and Cynomolgus monkeys, respectively, using LC-MS/MS bioanalysis. Preliminary toxicity studies in rats and Cynomolgus monkeys demonstrated that LCB36 is well tolerated. In conclusion, LCB36, composed of a BsAb that binds to two clinically validated targets, showed efficacy at well-tolerated doses and has the potential to increase event-free survival periods by reducing MRD. Citation Format: Wihak Kim, Namjeong Choi, Cul-Woong Chung, Hwanhee Oh. LCB36, a bi-specific antibody drug conjugate (BsADC) utilizing ConjuAll conjugation technology and proprietary prodrug payload selectively activated in cancer cells for treating B-cell blood cancers expressing CD20 and/or CD22 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1870.