| 1. |
- Mohajershojai, Tabassom
(author)
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Enhancing Cancer Treatment through Combination Therapies
- 2024
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Doctoral thesis (other academic/artistic)abstract
- Cancer, a complex disease marked by uncontrolled cell growth, is typically treated with surgery, chemotherapy, radiation therapy and immunotherapy, which can induce significant side effects by affecting healthy tissues. Targeted radionuclide therapy (TRT), where cancer-targeting molecules are equipped with radionuclides to enable cancer-specific radiotherapy, shows promise for treating advanced cancers by addressing both metastatic relapse and heterogeneous tumors. Combining TRT with targeted therapies offers a promising shift towards more effective and less toxic treatments. This thesis focuses on synergistically enhancing the therapeutic efficacy of TRT or chemotherapy through combination strategies with novel drugs that modulate DNA damage and/or interact with the immune system.In Paper I, we investigated the combination treatment of the chemotherapy drug cisplatin with the heat shock protein 90 (HSP90) inhibitor onalespib in vitro, using ovarian and head and neck cancer cells. Our findings demonstrated that onalespib enhances the therapeutic effects of cisplatin, reducing colony formation and migration, increasing apoptosis, and decreasing DNA damage response (DDR). Key proteins such as ATM, DNA-PKcs, and γH2AX were shown to play crucial roles in the therapeutic efficacy of the combination treatments.In Papers II and III, we characterized the synergy between the novel radioconjugate, 177Lu-DOTA-M5A, and onalespib in gastrointestinal cancer models in vitro and in vivo. While 177Lu-DOTA-M5A exhibited significant cellular uptake and therapeutic efficacy as monotherapy in 3D tumor spheroids and xenografts. The combination exhibited the most pronounced synergistic growth inhibitory effects in both settings with no adverse effects observed in vivo. PARP1 was identified as playing a pivotal role in the therapeutic outcomes.In Paper IV, we explored combining 177Lu-DOTA-M5A with PD-1 immune checkpoint blockade in an immunocompetent transgenic mouse model. The radioconjugate demonstrated high tumor uptake and potent therapeutic effects as monotherapy without depleting immune cells within the tumor microenvironment, while PD-1 blockade further enhanced its efficacy by prolonging survival and suppressing tumor growth. CD8+ T cells and pro-inflammatory macrophages (M1) were critical for these therapeutic effects and no myelotoxicity was observed with any treatments.In conclusion, we have investigated various combination treatment approaches aimed at enhancing therapeutic efficacy while mitigating side effects and drug resistance. We have evaluated the feasibility, toxicity, and benefits of these combinations in preclinical settings with promising results, underscoring the potential of integrating TRT into combination therapy.Further investigation is warranted as an increasing number of TRT and combination therapies are entering clinical trials.
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| 2. |
- Morgan, Daniel, et al.
(author)
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Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms
- 2020
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Journal article (peer-reviewed)abstract
- The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in cross-validated benchmarks and for an independent dataset of the same genes under a different perturbation design. The inferred GRN captures many known regulatory interactions central to cancer-relevant processes in addition to predicting many novel interactions, some of which were experimentally validated, thus providing mechanistic insights that are useful for future cancer research.
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| 3. |
- Roy, Ananya, et al.
(author)
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Serglycin as a potential biomarker for glioma : association of serglycin expression, extent of mast cell recruitment and glioblastoma progression
- 2017
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:15, s. 24815-24827
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Journal article (peer-reviewed)abstract
- Serglycin is an intracellular proteoglycan with a unique ability to adopt highly divergent structures by glycosylation with variable types of glycosaminoglycans (GAGs) when expressed by different cell types. Serglycin is overexpressed in aggressive cancers suggesting its protumorigenic role. In this study, we explored the expression of serglycin in human glioma and its correlation with survival and immune cell infiltration. We demonstrate that serglycin is expressed in glioma and that increased expression predicts poor survival of patients. Analysis of serglycin expression in a large cohort of low- and high-grade human glioma samples reveals that its expression is grade dependent and is positively correlated with mast cell (MC) infiltration. Moreover, serglycin expression in patient-derived glioma cells is significantly increased upon MC co-culture. This is also accompanied by increased expression of CXCL12, CXCL10, as well as markers of cancer progression, including CD44, ZEB1 and vimentin.In conclusion, these findings indicate the importance of infiltrating MCs in glioma by modulating signaling cascades involving serglycin, CD44 and ZEB1. The present investigation reveals serglycin as a potential prognostic marker for glioma and demonstrates an association with the extent of MC recruitment and glioma progression, uncovering potential future therapeutic opportunities for patients.
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| 4. |
- Susanto, Evelyn, et al.
(author)
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Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells
- 2020
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In: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 117:33, s. 20127-20138
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Journal article (peer-reviewed)abstract
- Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using In-duced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carry-ing a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, en-hanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we dem-onstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.
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| 5. |
- Xiong, Anqi, 1986-, et al.
(author)
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Nuclear Receptor Binding Protein 2 Is Downregulated in Medulloblastoma, and Reduces Tumor Cell Survival upon Overexpression
- 2020
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In: Cancers. - : MDPI AG. - 2072-6694. ; 12:6
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Journal article (peer-reviewed)abstract
- Pseudokinases, comprising 10% of the human kinome, are emerging as regulators of canonical kinases and their functions are starting to be defined. We previously identified the pseudokinase Nuclear Receptor Binding Protein 2 (NRBP2) in a screen for genes regulated during neural differentiation. During mouse brain development,NRBP2is expressed in the cerebellum, and in the adult brain, mainly confined to specific neuronal populations. To study the role of NRBP2 in brain tumors, we stained a brain tumor tissue array for NRPB2, and find its expression to be low, or absent, in a majority of the tumors. This includes medulloblastoma (MB), a pediatric tumor of the cerebellum. Using database mining of published MB data sets, we also find that NRBP2 is expressed at a lower level in MB than in the normal cerebellum. Recent studies indicate that MB exhibits frequent epigenetic alternations and we therefore treated MB cell lines with drugs inhibiting DNA methylation or histone deacetylation, which leads to an upregulation of NRBP2 mRNA expression, showing that it is under epigenetic regulation in cultured MB cells. Furthermore, forced overexpression of NRBP2 in MB cell lines causes a dramatic decrease in cell numbers, increased cell death, impaired cell migration and inhibited cell invasion in vitro. Taken together, our data indicate that downregulation of NRBP2 may be a feature by which MB cells escape growth regulation.
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| 6. |
- Adolphe, Christelle, et al.
(author)
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SOX9 Defines Distinct Populations of Cells in SHH Medulloblastoma but Is Not Required for Math1-Driven Tumor Formation
- 2021
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In: Molecular Cancer Research. - : American Association For Cancer Research (AACR). - 1541-7786 .- 1557-3125. ; 19:11, s. 1831-1839
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Journal article (peer-reviewed)abstract
- Medulloblastoma is the most common malignant pediatric brain tumor and there is an urgent need for molecularly targeted and subgroup-specific therapies. The stem cell factor SOX9, has been proposed as a potential therapeutic target for the treatment of Sonic Hedgehog medulloblastoma (SHH-MB) subgroup tumors, given its role as a downstream target of Hedgehog signaling and in functionally promoting SHH-MB metastasis and treatment resistance. However, the functional requirement for SOX9 in the genesis of medulloblastoma remains to be determined. Here we report a previously undocumented level of SOX9 expression exclusively in proliferating granule cell precursors ( GCP) of the postnatal mouse cerebellum, which function as the medulloblastoma-initiating cells of SHH-MBs. Wild-type GCPs express comparatively lower levels of SOX9 than neural stem cells and mature astroglia and SOX9(low) GCP-like tumor cells constitute the bulk of both infant (Math1Cre: Ptch1(lox/lox)) and adult (Ptch1(LacZ/+)) SHH-MB mouse models. Human medulloblastoma single-cell RNA data analyses reveal three distinct SOX9 populations present in SHH-MB and noticeably absent in other medulloblastoma subgroups: SOX9(+)MATH1(+) (GCP), SOX9(+)GFAP(+) (astrocytes) and SOX9(+)MATH1(+)GFAP(+) (potential tumor-derived astrocytes). To functionally address whether SOX9 is required as a downstream effector of Hedgehog signaling in medulloblastoma tumor cells, we ablated Sox9 using a Math1Cre model system. Surprisingly, targeted ablation of Sox9 in GCPs (Math1Cre:Sox9(lox/lox)) revealed no overt phenotype and loss of Sox9 in SHH-MB (Math1Cre:Ptch1(lox/lox);Sox9(lox/lox)) does not affect tumor formation.
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| 7. |
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| 8. |
- Bandopadhayay, Pratiti, et al.
(author)
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BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
- 2014
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 20:4, s. 912-925
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Journal article (peer-reviewed)abstract
- Purpose:MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.Experimental Design:We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.Results:Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.Conclusion:JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.
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| 9. |
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| 10. |
- Bengtsson, Niklas, et al.
(author)
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Fetal Iodine Deficiency and Schooling : A Replication of Field, Robles, and Torero (2009)
- 2020
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In: Scandinavian Journal of Economics. - : Wiley. - 0347-0520 .- 1467-9442. ; 122:2, s. 582-621
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Journal article (peer-reviewed)abstract
- Scholars have theorized that congenital health endowment is an important determinant of economic outcomes later in a person's life. Field, Robles, and Torero (2009, American Economic Journal: Applied Economics 1, 140-169) find large increases in educational attainment caused by a reduction of fetal iodine deficiency following a set of iodine supplementation programs in Tanzania. We revisit the Tanzanian iodine programs with a narrow and wide replication of the study by Field et al. We are able to exactly replicate the original results. We find, however, that the findings are sensitive to alternative specification choices and sample restrictions. We try to address some of these concerns in the wide replication; we increase the sample size fourfold, and we improve the precision of the treatment variable by incorporating new institutional and medical insights. Despite the improvements, no effect is found. We conclude that the available data do not provide sufficient power to detect a possible effect, as treatment assignment cannot be measured with sufficient precision.
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