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At least 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Ad-apoptin inhibits glycolysis, migration and invasion in lung cancer cells targeting AMPK/mTOR signaling pathway

Ad-apoptin is a recombinant oncolytic adenovirus constructed by our laboratory that can express apoptin. It can selectively kill tumor cells without damaging normal cells. This study investigated the effects of Ad-apoptin on glycolysis, migration and invasion of non-small cell lung cancer. Cell viability and apoptosis were detected by CCK-8 and flow cytometry, respectively. Glycolysis was investigated by glucose consumption, lactic acid production and glycolytic key enzyme protein levels. Migration and invasion were evaluated via wound healing, transwell assays and epithelial-mesenchymal transition (EMT) protein levels. The interaction between apoptin and AMPK was detected by Co-IP. A nude mice tumor model was established to investigate the anti-cancer role of Ad-apoptin in vivo. The results showed that Ad-apoptin inhibits cell viability and induces apoptosis of A549 and NCI–H23 cells. Ad-apoptin can reduce the glucose uptake and lactic production in lung cancer cells, and reduce the expression of related glycolysis-limiting enzymes. At the same time, Ad-apoptin inhibited the migration and invasion of lung cancer. Immunoprecipitation showed that apoptin and AMPK could interact directly. Moreover, knockdown of AMPK significantly attenuated the inhibitory effect of Ad-apoptin on glycolysis, migration and invasion of A549 and NCI–H23 cells. Ad-apoptin can inhibit the growth of tumors in nude mice. Compared with the control group, Ad-apoptin had a significant inhibitory effect on AMPK knockdown tumors. The immunohistochemical results of tumor tissues were consistent with those in vitro. Collectively, Ad-apoptin targets AMPK and inhibits glycolysis, migration and invasion of lung cancer cells through the AMPK/mTOR signaling pathway. This suggests that Ad-apoptin may have therapeutic potential for lung cancer by targeting AMPK activation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Effects of periodontitis on postoperative pneumonia in patients with lung and esophageal cancer

Abstract Background Few studies have been conducted on the relationship between chronic periodontitis and postoperative pneumonia (POP) in patients with lung and esophageal cancer. Furthermore, it remains controversial as to whether improving the periodontal condition of patients with lung and esophageal cancer before surgery reduces the incidence of POP. This retrospective study was conducted to assess the effects of periodontal therapy in patients with lung and esophageal cancer to prevent POP. Methods A total of 265 patients with lung or esophageal cancer complicated with chronic periodontitis who underwent open thoracotomy between July 2015 and June 2019 were selected and given the choice of being in the experimental or control group. A total of 141 participants in the experimental group received periodontal therapy, and 124 participants in the control group did not receive periodontal therapy. All clinical data of participants in both groups were retrospectively studied to determine the incidence of POP on the 30th day after discharge from hospital. Results Eight patients in the experimental and six in the control group, respectively, were excluded from the study. It was found that four of the 133 patients suffered from POP in the experimental group (incidence: 3.01%). A total of 18 of 118 patients in the control group had a pulmonary infection (incidence: 15.25%). POP incidence in the experimental group was significantly lower than that in the control group, and in the level analysis of different types of periodontitis, surgical methods, and diseases ( p < 0.05). Conclusions Periodontal treatment is associated with a lower incidence of POP following lung and esophageal cancer surgery. Improving the periodontal condition of patients helps prevent POP. The presence of periodontitis is an important predisposing factor for POP in patients after open thoracotomy. Periodontal examination and therapy are recommended before the surgical treatment of lung or esophageal cancer.

Jia, Chunling↗
DOE OSTI2022

Novel Anti-LY6G6D/CD3 T-Cell–Dependent Bispecific Antibody for the Treatment of Colorectal Cancer

Abstract New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer. Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch-repair–deficient or microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) colorectal cancer have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC. In this article, we describe the discovery of a novel T-cell–dependent bispecific antibody (TDB) targeting tumor-associated antigen LY6G6D, LY6G6D-TDB, for the treatment of colorectal cancer. RNAseq analysis showed that LY6G6D was differentially expressed in colorectal cancer with high prevalence in MSS and MSI-L subsets, whereas LY6G6D expression in normal tissues was limited. IHC confirmed the elevated expression of LY6G6D in primary and metastatic colorectal tumors, whereas minimal or no expression was observed in most normal tissue samples. The optimized LY6G6D-TDB, which targets a membrane-proximal epitope of LY6G6D and binds to CD3 with high affinity, exhibits potent antitumor activity both in vitro and in vivo. In vitro functional assays show that LY6G6D-TDB–mediated T-cell activation and cytotoxicity are conditional and target dependent. In mouse xenograft tumor models, LY6G6D-TDB demonstrates antitumor efficacy as a single agent against established colorectal tumors, and enhanced efficacy can be achieved when LY6G6D-TDB is combined with PD-1 blockade. Our studies provide evidence for the therapeutic potential of LY6G6D-TDB as an effective treatment option for patients with colorectal cancer.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1993

Screening for prostate cancer

Despite recent advances in both the survival and cure rates for many forms of cancer, unfortunately the same has not been true for prostate cancer. In fact, the age-adjusted death rate from prostate cancer has not significantly improved since 1949, and prostate cancer remains the most common cancer in American men, causing the second highest cancer mortality rate. Topics discussed include the following: serum testosterone levels; diagnosis; mortality statistics; prostate-sppecific antigen (PSA) tests; and the Occupational Medicine Services policy at LeRC.

Weirich, Stephen A.↗
NASA NTRS2002

Cancer Risk Assessment for Space Radiation

Predicting the occurrence of human cancer following exposure to any agent causing genetic damage is a difficult task. This is because the uncertainty of uniform exposure to the damaging agent, and the uncertainty of uniform processing of that damage within a complex set of biological variables, degrade the confidence of predicting the delayed expression of cancer as a relatively rare event within any given clinically normal individual. The radiation health research priorities for enabling long-duration human exploration of space were established in the 1996 NRC Report entitled "Radiation Hazards to Crews of Interplanetary Missions: Biological Issues and Research Strategies". This report emphasized that a 15-fold uncertainty in predicting radiation-induced cancer incidence must be reduced before NASA can commit humans to extended interplanetary missions. That report concluded that the great majority of this uncertainty is biologically based, while a minority is physically based due to uncertainties in radiation dosimetry and radiation transport codes. Since that report, the biologically based uncertainty has remained large, and the relatively small uncertainty associated with radiation dosimetry has increased due to the considerations raised by concepts of microdosimetry. In a practical sense, however, the additional uncertainties introduced by microdosimetry are encouraging since they are in a direction of lowered effective dose absorbed through infrequent interactions of any given cell with the high energy particle component of space radiation. The biological uncertainty in predicting cancer risk for space radiation derives from two primary facts. 1) One animal tumor study has been reported that includes a relevant spectrum of particle radiation energies, and that is the Harderian gland model in mice. Fact #1: Extension of cancer risk from animal models, and especially from a single study in an animal model, to humans is inherently uncertain. 2) One human database is predominantly used for assessing cancer risk caused by space radiation, and that is the Japanese atomic bomb survivors. Fact #2: The atomic-bomb-survivor database, itself a remarkable achievement, contains uncertainties. These include the actual exposure to each individual, the radiation quality of that exposure, and the fact that the exposure was to acute doses of predominantly low-LET radiation, not to chronic exposures of high-LET radiation expected on long-duration interplanetary manned missions.

Richmond, Robert C.↗
NASA NTRS2000

Breast Cancer Detection

The BioScan System was developed by OmniCorder Technologies, Inc. at the Jet Propulsion Laboratory. The system is able to locate cancerous lesions by detecting the cancer's ability to recruit a new blood supply. A digital sensor detects infrared energy emitted from the body and identifies the minute differences accompanying the blood flow changes associated with cancerous cells. It also has potential use as a monitoring device during cancer treatment. This technology will reduce the time taken to detect cancerous cells and allow for earlier intervention, therefore increasing the overall survival rates of breast cancer patients.

Source record↗
NASA NTRS2002

Space Radiation Cancer Risk Projections for Exploration Missions: Uncertainty Reduction and Mitigation

In this paper we discuss expected lifetime excess cancer risks for astronauts returning from exploration class missions. For the first time we make a quantitative assessment of uncertainties in cancer risk projections for space radiation exposures. Late effects from the high charge and energy (HZE) ions present in the galactic cosmic rays including cancer and the poorly understood risks to the central nervous system constitute the major risks. Methods used to project risk in low Earth orbit are seen as highly uncertain for projecting risks on exploration missions because of the limited radiobiology data available for estimating HZE ion risks. Cancer risk projections are described as a product of many biological and physical factors, each of which has a differential range of uncertainty due to lack of data and knowledge. Monte-Carlo sampling from subjective error distributions represents the lack of knowledge in each factor to quantify risk projection overall uncertainty. Cancer risk analysis is applied to several exploration mission scenarios. At solar minimum, the number of days in space where career risk of less than the limiting 3% excess cancer mortality can be assured at a 95% confidence level is found to be only of the order of 100 days.

Cucinotta, Francis↗
NASA NTRS1999

An ecologic study of dietary links to prostate cancer

BACKGROUND: The etiology of prostate cancer has not been fully resolved in the scientific and medical literature, although the non-fat portion of milk and calcium are emerging as leading dietary risk factors, with lycopene (found in tomatoes) and vitamin D apparently being risk reduction factors. METHODS: The ecologic (multi-country statistical) approach is used to study dietary links to prostate cancer. Mortality data from 1986 for various age groups in 41 countries are compared with national consumer macronutrient supply values for 1983 and tomato supply values for 1985. RESULTS: For 28 countries with more than five Kcal/day of tomatoes in the consumer supply, a linear combination of non-fat milk (risk factor) and tomatoes (risk reduction factor) was found to have the highest statistical association with prostate cancer mortality rates for men over the age of 35, with the Pearson regression coefficient (R2) for those aged 65-74 years = 0.67 and p < 0.001. For the 13 countries with fewer than six Kcal/day of tomatoes, non-fat milk had the highest association (R2 = 0.92, p < 0.001 for men aged 65-74 years). For 41 countries combined, the non-fat portion of milk had the highest association with prostate cancer mortality rates (R2 = 0.73, p < 0.001 for men aged 65-74 years). CONCLUSIONS: These results support the results of several cohort studies which found the non-fat portion of milk to have the highest association with prostate cancer, likely due to the calcium, and tomatoes to reduce the risk of prostate cancer, most likely due to lycopene.

Diet/adverse effects↗
NASA NTRS2004

Hematopoietic Stem Cell Therapy to Countermeasure Cancer in Astronauts during Exploration of Deep Space

Exposure to cosmic radiation can cause chromosomal mutations, which may lead to cancer in astronauts engaged in space exploration. Therefore, our goals are to develop countermeasures to prevent space-induced cancer using hematopoietic stem cell therapy (HSCT) and gene therapy. This presentation focuses on HSCT for cancer. Our previous experiments on a simulated, space-induced immuno-deficiency model (mouse hind limb unloading ) indicated that transplanted hematopoietic stem cells (HSCs) could enhance the host's immunity by effectively eliminating bacterial infection (Ohi S, et. al. J Grav Physiol 10, P63-64, 2003; Ohi S, et. al. Proceedings of the Space Technology and Applications International Forum (STAIF) . American Institute of Physics, New York, pp. 938-950, 2004). Hence, we hypothesized that the HSCs might be effective in combating cancer as well. Studies of cocultured mouse HSCs with beta-galactosidase marked rat gliosarcoma spheroids (9L/lacZ), a cancer model, indicated antagonistic interactions , resulting in destruction of the spheroids by HSCs. Trypan Blue dye-exclusion assays were consistent with the conclusion. These results show potential usehlness of HSCT for cancer. Currently, the NASA Hydrodynamic Focusing Bioreactor (HFB), a space analog tissue/cell culture system, is being used to study invasion of the gliosarcoma (GS) spheroids into mouse brain with or without co-cultured HSCs. This may simulate the metastasis of gliosarcoma to brain. There is a tendency for the HSCs to inhibit invasion of GS spheroids into brain, as evidenced by the X-gal staining.

Ohi, S.↗
NASA NTRS2012

Space Radiation Cancer Risks and Uncertainities for Different Mission Time Periods

Space radiation consists of solar particle events (SPEs), comprised largely of medium energy protons (less than several hundred MeV); and galactic cosmic ray (GCR), which includes high energy protons and high charge and energy (HZE) nuclei. For long duration missions, space radiation presents significant health risks including cancer mortality. Probabilistic risk assessment (PRA) is essential for radiation protection of crews on long term space missions outside of the protection of the Earth s magnetic field and for optimization of mission planning and costs. For the assessment of organ dosimetric quantities and cancer risks, the particle spectra at each critical body organs must be characterized. In implementing a PRA approach, a statistical model of SPE fluence was developed, because the individual SPE occurrences themselves are random in nature while the frequency distribution of SPEs depends strongly upon the phase within the solar activity cycle. Spectral variability of SPEs was also examined, because the detailed energy spectra of protons are important especially at high energy levels for assessing the cancer risk associated with energetic particles for large events. An overall cumulative probability of a GCR environment for a specified mission period was estimated for the temporal characterization of the GCR environment represented by the deceleration potential (theta). Finally, this probabilistic approach to space radiation cancer risk was coupled with a model of the radiobiological factors and uncertainties in projecting cancer risks. Probabilities of fatal cancer risk and 95% confidence intervals will be reported for various periods of space missions.

Kim,Myung-Hee Y.↗
NASA NTRS2013

NASA Models of Space Radiation Induced Cancer, Circulatory Disease, and Central Nervous System Effects

The risks of late effects from galactic cosmic rays (GCR) and solar particle events (SPE) are potentially a limitation to long-term space travel. The late effects of highest concern have significant lethality including cancer, effects to the central nervous system (CNS), and circulatory diseases (CD). For cancer and CD the use of age and gender specific models with uncertainty assessments based on human epidemiology data for low LET radiation combined with relative biological effectiveness factors (RBEs) and dose- and dose-rate reduction effectiveness factors (DDREF) to extrapolate these results to space radiation exposures is considered the current "state-of-the-art". The revised NASA Space Risk Model (NSRM-2014) is based on recent radio-epidemiology data for cancer and CD, however a key feature of the NSRM-2014 is the formulation of particle fluence and track structure based radiation quality factors for solid cancer and leukemia risk estimates, which are distinct from the ICRP quality factors, and shown to lead to smaller uncertainties in risk estimates. Many persons exposed to radiation on earth as well as astronauts are life-time never-smokers, which is estimated to significantly modify radiation cancer and CD risk estimates. A key feature of the NASA radiation protection model is the classification of radiation workers by smoking history in setting dose limits. Possible qualitative differences between GCR and low LET radiation increase uncertainties and are not included in previous risk estimates. Two important qualitative differences are emerging from research studies. The first is the increased lethality of tumors observed in animal models compared to low LET radiation or background tumors. The second are Non- Targeted Effects (NTE), which include bystander effects and genomic instability, which has been observed in cell and animal models of cancer risks. NTE's could lead to significant changes in RBE and DDREF estimates for GCR particles, and the potential effectiveness of radiation mitigator's. The NSRM- 2014 approaches to model radiation quality dependent lethality and NTE's will be described. CNS effects include both early changes that may occur during long space missions and late effects such as Alzheimer's disease (AD). AD effects 50% of the population above age 80-yr, is a degenerative disease that worsens with time after initial onset leading to death, and has no known cure. AD is difficult to detect at early stages and the small number of low LET epidemiology studies undertaken have not identified an association with low dose radiation. However experimental studies in mice suggest GCR may lead to early onset AD. We discuss modeling approaches to consider mechanisms whereby radiation would lead to earlier onset of occurrence of AD. Biomarkers of AD include amyloid beta (A(Beta)) plaques, and neurofibrillary tangles (NFT) made up of aggregates of the hyperphosphorylated form of the micro-tubule associated, tau protein. Related markers include synaptic degeneration, dentritic spine loss, and neuronal cell loss through apoptosis. Radiation may affect these processes by causing oxidative stress, aberrant signaling following DNA damage, and chronic neuroinflammation. Cell types to be considered in multi-scale models are neurons, astrocytes, and microglia. We developed biochemical and cell kinetics models of DNA damage signaling related to glycogen synthase kinase-3(Beta) (GSK3(Beta)) and neuroinflammation, and considered multi-scale modeling approaches to develop computer simulations of cell interactions and their relationships to A(Beta) plaques and NFTs. Comparison of model results to experimental data for the age specific development of A(Beta) plaques in transgenic mice will be discussed.

Cucinotta, Francis A.↗
NASA NTRS2017

Skin-Based DNA Repair Phenotype for Cancer Risk from GCR in Genetically Diverse Populations

Predicting cancer risk associated with cosmic radiation remains a mission-critical challenge for NASA radiation health scientists and mission planners. Epidemiological data are lacking and risk methods do not take individual radiation sensitivity into account. In our approach we hypothesize that genetic factors strongly influence risk of cancer from space radiation and that biomarkers reflecting DNA damage and cell death are ideal tools to predict risk and monitor potential health effects post-flight. At this workshop, we will be reporting the work we have done over the first 9 months of this proposal. Skin cells from 15 different strains of mice already characterized for radiation-induced cancer sensitivity (B6C3F; BALB/cByJ, C57BL/6J, CBA/CaJ, C3H/HeMsNrsf), and 10 strains from the DOE collaborative cross-mouse model were expanded from ear biopsy and cultivated until Passage 3. On average, 3 males and 3 females for each strain were expanded and frozen for further characterization at the NSRL beam line during the NSRL16C run for three LET (350 MeV/n Si, 350 MeV/n Ar and 600 MeV/n Fe) and two ion fluences (1 and 3 particles per cell). The mice work has established new metrics for the usage of Radiation Induced Foci as a marker for various aspect of DNA repair deficiencies. In year 2, we propose to continue characterization of the mouse lines with low LET to identify loci specific to high- versus low- LET and establish genetic linkage for the various DNA repair biomarkers. Correlation with cancer risk from each animals strain and gender will also be investigated. On the human side, we will start characterizing the DNA damage response induced ex-vivo in 200 human's blood donors for radiation sensitivity with a tentative 500 donors by the end of this project. All ex-vivo phenotypic data will be correlated to genetic characterization of each individual human donors using SNP arrays characterization as done for mice. Similarly, ex-vivo phenotypic features from mice will be associated to cancer risk, to identify which biomarkers correlate the most with cancer risk. Genetic traits across humans will also be associated to radiation phenotypic features as a function of age and gender.

radiation space biology↗
DOE OSTI2025

Matrix Metalloproteinases as Candidate Antigenic Determinants for Anti‐Tumor Autoantibodies in Human Ovarian Cancer: A Post Hoc Analysis

Circulating antibodies in patients with cancer can facilitate the identification of accessible epitopes on autoantigens expressed by tumors. To identify previously unrecognized protein targets in ovarian cancer, we computationally assessed a heptapeptide consensus motif (VPELGHE, flanked by two cysteine residues yielding a cyclic nonapeptide under oxidizing conditions) previously discovered via phage display-based epitope mapping of autoantibodies in patients. Eight proteins associated with ovarian cancer encompass amino acid sequences similar to the consensus motif and were, therefore, considered as candidate native autoantigens. Among these candidate targets, however, matrix metalloproteinase 14 (MMP14) demonstrates gene expression that is both high and negatively correlated with survival in ovarian cancer patient cohorts. MMP14 protein levels are also stable in tumor versus non-tumor tissues. Moreover, the corresponding heptapeptide mimic in MMP14 occurs within an α-helical secondary structural element observed in its catalytic domain. These findings demonstrate that a subset of patient-derived autoantibodies may interact with a previously unknown antigenic epitope found in MMP14 and other MMPs, thereby providing opportunities for the development of new targeted agents.

Biochemistry & Molecular Biology↗
DOE OSTI2022

In search of autophagy biomarkers in breast cancer: Receptor status and drug agnostic transcriptional changes during autophagy flux in cell lines

Autophagy drives drug resistance and drug-induced cancer cell cytotoxicity. Targeting the autophagy process could greatly improve chemotherapy outcomes. The discovery of specific inhibitors or activators has been hindered by challenges with reliably measuring autophagy levels in a clinical setting. We investigated drug-induced autophagy in breast cancer cell lines with differing ER/PR/Her2 receptor status by exposing them to known but divergent autophagy inducers each with a unique molecular target, tamoxifen, trastuzumab, bortezomib or rapamycin. Differential gene expression analysis from total RNA extracted during the earliest sign of autophagy flux showed both cell- and drug-specific changes. We analyzed the list of differentially expressed genes to find a common, cell- and drug-agnostic autophagy signature. Twelve mRNAs were significantly modulated by all the drugs and 11 were orthogonally verified with Q-RT-PCR (Klhl24, Hbp1, Crebrf, Ypel2, Fbxo32, Gdf15, Cdc25a, Ddit4, Psat1, Cd22, Ypel3). The drug agnostic mRNA signature was similarly induced by a mitochondrially targeted agent, MitoQ. In-silico analysis on the KM-plotter cancer database showed that the levels of these mRNAs are detectable in human samples and associated with breast cancer prognosis outcomes of Relapse-Free Survival in all patients (RSF), Overall Survival in all patients (OS), and Relapse-Free Survival in ER + Patients (RSF ER + ). High levels of Klhl24, Hbp1, Crebrf, Ypel2, CD22 and Ypel3 were correlated with better outcomes, whereas lower levels of Gdf15, Cdc25a, Ddit4 and Psat1 were associated with better prognosis in breast cancer patients. This gene signature uncovers candidate autophagy biomarkers that could be tested during preclinical and clinical studies to monitor the autophagy process.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Pan-cancer evaluation of clinical value of mitotic network activity index (MNAI) and its predictive value for immunotherapy

Increased mitotic activity is associated with the genesis and aggressiveness of many cancers. To assess the clinical value of mitotic activity as prognostic biomarker, we performed a pan-cancer study on the mitotic network activity index (MNAI) constructed based on 54-gene mitotic apparatus network. Our pan-cancer assessment on TCGA (33 tumor types, 10,061 patients) and validation on other publicly available cohorts (23 tumor types, 9,209 patients) confirmed the significant association of MNAI with overall survival, progression-free survival, and other prognostic endpoints in multiple cancer types, including lower-grade gliomas (LGG), breast invasive carcinoma (BRCA), as well as many others. We also showed significant association between MNAI and genetic instability, which provides a biological explanation of its prognostic impact at pan-cancer landscape. Our association analysis revealed that patients with high MNAI benefitted more from anti-PD-1 and Anti-CTLA-4 treatment. In addition, we demonstrated that multimodal integration of MNAI and the AI-empowered Cellular Morphometric Subtypes (CMS) significantly improved the predictive power of prognosis compared to using MNAI and CMS alone. Our results suggest that MNAI can be used as a potential prognostic biomarker for different tumor types toward different clinical endpoints, and multimodal integration of MNAI and CMS exceeds individual biomarker for precision prognosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

NCAPH drives breast cancer progression and identifies a gene signature that predicts luminal a tumour recurrence

Luminal A tumours generally have a favourable prognosis but possess the highest 10-year recurrence risk among breast cancers. Additionally, a quarter of the recurrence cases occur within 5 years post-diagnosis. Identifying such patients is crucial as long-term relapsers could benefit from extended hormone therapy, while early relapsers might require more aggressive treatment. We conducted a study to explore non-structural chromosome maintenance condensin I complex subunit H’s (NCAPH) role in luminal A breast cancer pathogenesis, both in vitro and in vivo, aiming to identify an intratumoural gene expression signature, with a focus on elevated NCAPH levels, as a potential marker for unfavourable progression. Our analysis included transgenic mouse models overexpressing NCAPH and a genetically diverse mouse cohort generated by backcrossing. A least absolute shrinkage and selection operator (LASSO) multivariate regression analysis was performed on transcripts associated with elevated intratumoural NCAPH levels. We found that NCAPH contributes to adverse luminal A breast cancer progression. The intratumoural gene expression signature associated with elevated NCAPH levels emerged as a potential risk identifier. Transgenic mice overexpressing NCAPH developed breast tumours with extended latency, and in Mouse Mammary Tumor Virus (MMTV)-NCAPH ErbB2 double-transgenic mice, luminal tumours showed increased aggressiveness. High intratumoural Ncaph levels correlated with worse breast cancer outcome and subpar chemotherapy response. A 10-gene risk score, termed Gene Signature for Luminal A 10 (GSLA10), was derived from the LASSO analysis, correlating with adverse luminal A breast cancer progression. The GSLA10 signature outperformed the Oncotype DX signature in discerning tumours with unfavourable outcomes, previously categorised as luminal A by Prediction Analysis of Microarray 50 (PAM50) across three independent human cohorts. This new signature holds promise for identifying luminal A tumour patients with adverse prognosis, aiding in the development of personalised treatment strategies to significantly improve patient outcomes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Analysis of tumor-immune functional responses in a mathematical model of neoantigen cancer vaccines

Cancer neoantigen vaccines have emerged as a promising approach to stimulating the immune system to fight cancer. We propose a simple model including key elements of cancer-immune interactions and conduct a phase plane analysis to understand the immunological mechanisms of cancer neoantigen vaccines. Analytical results are obtained for two widely used functional forms that represent the killing rate of tumor cells by immune cells: the law of mass action (LMA) and the dePillis-Radunskaya Law (LPR). Using the LMA, our results reveal that a slowly growing tumor can escape the immune surveillance and that there is a unique periodic solution. The LPR offers richer dynamics, in which tumor elimination and uncontrolled tumor growth are both present. We show that tumor elimination requires sufficient number of initial activated T cells in relationship to the malignant cells, which lends support to using the neoantigen cancer vaccine as an adjuvant therapy after the primary tumor is surgically removed or treated using radiotherapy. We also derive a sufficient condition for uncontrolled tumor growth under the assumption of the LPR. Here, the juxtaposition of analyses with these two different choices for the killing rate function highlights their importance on model behavior and biological implications, by which we hope to spur further theoretical and experimental work to understand mechanisms underlying different functional forms for the killing rate.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Poly( N -vinylpyrrolidone)- block -Poly(dimethylsiloxane)- block -Poly( N -vinylpyrrolidone) Triblock Copolymer Polymersomes for Delivery of PARP1 siRNA to Breast Cancers

Nearly 20% of HER2-positive breast cancers develop resistance to HER2-targeted therapies requiring the use of advanced therapies. Silencing RNA therapy may be a powerful modality for treating resistant HER2 cancers due to its high specificity and low toxicity. However, the systemic administration of siRNAs requires a safe and efficient delivery platform because of siRNA’s low stability in physiological fluids, inefficient cellular uptake, immunoreactivity, and rapid clearance. We have developed theranostic polymeric vesicles to overcome these hurdles for encapsulation and delivery of small functional molecules and PARP1 siRNA for in vivo delivery to breast cancer tumors. The 100 nm polymer vesicles were assembled from biodegradable and non-ionic poly(N-vinylpyrrolidone) 14 -block-poly(dimethylsiloxane) 47 -block-poly(N-vinylpyrrolidone) 14 triblock copolymer PVPON 14 -PDMS 47 -PVPON 14 using nanoprecipitation and thin-film hydration. We demonstrated that the vesicles assembled from the copolymer covalently tagged with the Cy5.5 fluorescent dye for in vivo imaging could also encapsulate the model drug with high loading efficiency (40%). The dye-loaded vesicles were accumulated in tumors after 18 h circulation in 4TR breast tumor-bearing mice via passive targeting. We found that PARP1 siRNA encapsulated into the vesicles was released intact (13%) into solution by the therapeutic ultrasound treatment as quantified by gel electrophoresis. Additionally, the PARP1 siRNA-loaded polymersomes inhibited the proliferation of MDA-MB-361TR cells by 34% after 6 days of treatment by suppressing the NF-kB signaling pathway, unlike their scrambled siRNA-loaded counterparts. Finally, the treatment by PARP1 siRNA-loaded vesicles prolonged the survival of the mice bearing 4T1 breast cancer xenografts, with the 4-fold survival increase, unlike the untreated mice after 3 weeks following the treatment. These biodegradable, non-ionic PVPON 14 -PDMS 47 -PVPON 14 polymeric nanovesicles capable of the efficient encapsulation and delivery of PARP1 siRNA to successfully knock down PARP1 in vivo can provide an advanced platform for the development of precision-targeted therapeutic carriers, which could help develop highly effective drug delivery nanovehicles for breast cancer gene therapy.

60 APPLIED LIFE SCIENCES↗