Biology subjects

Kommoss, F.

Publications and source records attributed to Kommoss, F..

3 recordsLinked to original sources

bioRxiv2024

Somatic gene delivery for flexible in vivo modeling of high-risk sarcoma

A particular challenge hampering therapeutic advancements for high-risk sarcoma patients is the broad spectrum of molecularly distinct sarcoma entities and the corresponding lack of suitable model systems to recapitulate and study these diseases. To overcome this predicament, we developed a novel genetically-controlled, yet versatile mouse modeling platform allowing delivery of different genetic lesions by electroporation (EPO) of the thigh muscle wildtype mice. This optimized sarcoma EPO-GEMM (EPO-based genetically engineered mouse model) platform allowed the generation of ten biologically distinct sarcoma entities, including Synovial Sarcoma (SS), fusion-positive and fusion-negative Rhabdomyosarcoma (RMS), Alveolar Soft Part Sarcoma (ASPS), Undifferentiated Pleomorphic Sarcoma (UPS) and Infantile Fibrosarcoma (IFS). Comprehensive molecular profiling and cross-species analyses confirmed faithful recapitulation of the human disease, including the expression of relevant immunotherapy targets. Syngeneic allografting enabled reliable preservation and scalability of Sarcoma-EPO-GEMMs for treatment trials, such as B7-H3-directed CAR-T cell therapy in an immunocompetent background.

cancer biology↗

bioRxiv2023

Landscape of super-enhancers in small cell carcinoma of the ovary, hypercalcemic type and efficacy of targeting with natural product triptolide

PurposeSmall cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare form of ovarian cancer affecting young women and girls. SCCOHT is driven by loss of both SWI/SNF ATPases SMARCA4 and SMARCA2, having major effects on enhancer landscapes. Super-enhancers are a distinct subset of enhancer clusters frequently associated with oncogenes in cancer. Experimental DesignSCCOHT cell lines and PDX models were interrogated for super-enhancer landscape with H3K27ac CUT&RUN integrated with RNAseq data for associated oncogene analysis. IHC staining and drug efficacy studies in PDX models demonstrate clinical translatability. ResultsHere we discovered key distinctions between SWI/SNF chromatin occupancy following SMARCA4 restoration at enhancer vs. super-enhancer sites and characterized putative oncogene expression driven by super-enhancer activity. SCCOHT super-enhancer target genes were particularly enriched in developmental processes, most notably nervous system development. We found high sensitivity of SCCOHT cell lines to triptolide, a small molecule that targets the XPB subunit of the transcription factor II H (TFIIH) complex, found at super-enhancers. Triptolide inhibits expression of many super-enhancer associated genes, including oncogenes. Notably, SALL4 expression is significantly decreased following short triptolide treatment, and its RNA expression was high in SCCOHT tumors relative to other ovarian cancers. In SCCOHT patient-derived xenograft models, triptolide and its prodrug derivative minnelide are particularly effective in inhibiting tumor growth. ConclusionsThese results demonstrate the key oncogenic role of super-enhancer activity following epigenetic dysfunction in SCCOHT, which can be effectively targeted through inhibition of its functional components, such as TFIIH inhibition with triptolide. Statement of Translational RelevanceThis work identifies a potential therapeutic strategy for small cell carcinoma of the ovary-hypercalcemic type (SCCOHT), a rare and aggressive ovarian cancer affecting young women and children. This study highlights the role of the loss of SWI/SNF ATPase SMARCA4 in altering super-enhancers to promote high oncogene expression. We discovered that SCCOHT cells exhibited high sensitivity to triptolide, a small molecule derived from Tripterygium wilfordii, which targets the XPB subunit of the transcription factor II H (TFIIH) complex found at super-enhancers. Triptolide inhibits the expression of super-enhancer-associated genes, including oncogenes like SALL4, which is highly expressed in SCCOHT. Moreover, in SCCOHT patient-derived xenograft models, triptolide and its derivative minnelide effectively inhibited tumor growth. These findings suggest that targeting super-enhancer activity could be a promising therapeutic approach for SCCOHT, offering potential clinical benefits to patients who currently face limited treatment options and poor outcomes.

cancer biology↗

bioRxiv2019

Arginine depletion through ADI-PEG20 to treat argininosuccinate synthase deficient ovarian cancer, including small cell carcinoma of the ovary, hypercalcemic type

PurposeMany rare ovarian cancer subtypes such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) have poor prognosis due to their aggressive nature and resistance to standard platinum and taxane based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targetable vulnerabilities in rare ovarian cancer subtypes. Experimental DesignWe compared the global proteomic landscape of six cases each of endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), and SCCOHT to the most common subtype high grade serous ovarian cancer (HGSC) to identify potential therapeutic targets. Immunohistochemistry of tissue microarrays were used as validation of ASS1 deficiency. The efficacy of arginine-depriving therapeutic ADI-PEG20 was assessed in vitro using cell lines and patient derived xenograft mouse models representing SCCOHT. ResultsGlobal proteomic analysis identified low ASS1 expression in ENOC, CCOC, and SCCOHT compared to HGSC. Low ASS1 levels were validated through IHC in a large patient cohort. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 2/15 cases, and expressed in less than 5% of the tumor cells in 8/15 cases. ASS1 deficient ovarian cancer cells were sensitive to ADI-PEG20 treatment regardless of subtype in vitro. Furthermore, in two cell line mouse xenograft models and one patient derived mouse xenograft model of SCCOHT, once a week treatment of ADI-PEG20 (30mg/kg and 15mg/kg) inhibited tumor growth in vivo. ConclusionsPreclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers including SCCOHT. Translational relevanceMany rare ovarian cancers lack effective management strategies and are resistant to the standard platinum- and taxane-based chemotherapy. Thus, for a rare ovarian cancer subtype like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) - an aggressive malignancy affecting young women in their twenties, effective targeted therapeutics are urgently needed. We used global proteomics to identify a deficiency in arginosuccinate synthase (ASS1) as a common feature among some rare ovarian cancer subtypes. Using in-vitro and in-vivo models, we demonstrated that the arginine-depriving investigational agent ADI-PEG20 effectively inhibited cell growth in ASS1 deficient ovarian cancers including SCCOHT, establishing it as a potential therapeutic agent for rare ovarian cancer subtypes deficient in ASS1. Further clinical investigation is warranted.

cancer biology↗