218 research outputs found
Abstract 5103: The dark cancer kinome - untapped opportunities for the development of novel drugs
No full textAbstract Kinases are firmly established drug targets in cancer. There are currently 44 FDA approved kinase drug and hundreds of compounds are in clinical development. However, less than 10% of the Kinome is currently targeted and a large proportion is considered understudied by the NIH Illuminating the Druggable Genome Program (https://druggablegenome.net/). No small molecule inhibitors are known for these “dark” proteins, yet many may be opportune novel cancer targets.We developed a computational pipeline to identify and prioritize understudied kinases as cancer drug targets. We analyzed the complete set of tumors in The Cancer Genome Atlas (TCGA). For 33 different cancers we performed differential expression analysis and identified 39 dark kinases that exhibit significant upregulation in at least four types. Using co-expression analysis we built functional networks prioritizing drug targets. To identify small molecules that reverse their expression levels, we leveraged transcriptional response signatures obtained from dozens of human cancer cell lines exposed to tens of thousands of small molecules from the Library of Integrated Network-based Cellular Signatures (LINCS). To identify small molecules that directly bind to and inhibit dark kinases, we have have combined an advanced AI (artificial intelligence) model trained on activity data from across the Kinome with structure-based simulations.Using the computational pipeline, we identified the dark Ca2+/Calmodulin dependent kinase PNCK as the most differentially overexpressed kinase in kidney cancer patients. Our analyses have demonstrated statistically significant correlation between PNCK mRNA levels and various clinical and pathological outcomes, including histologic grade, clinical staging and overall survival. We have confirmed high levels of PNCK expression in 5 renal cell carcinoma cell lines (Caki-1, ACHN, 786-O, A704 and A498). Knockdown and overexpression studies have suggested PNCK and the CaMK pathway may contribute to cellular proliferation and cell cycle progression. We have applied our AI-based screening pipeline to a library of >20 million commercially available compounds and confirmed three PNCK inhibiting chemotypes. In summary, using a novel computational pipeline, we have identified and experimentally validated PNCK as a prospective novel drug target in an understudied pathway that is highly upregulated in kidney cancer. We identified first in class small molecules that target this previously dark kinase as prospective starting points for optimization into a clinical candidate. Citation Format: Derek J. Essegian, Rimpi Khurana, Vasileios Stathias, Valery Chavez, Jaime R. Merchan, Stephan Schürer. The dark cancer kinome - untapped opportunities for the development of novel drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5103
Organisational risks matter and should be discussed during consent: survey of 980 neurosurgery patients from the UK
No full textIntroduction
During consent, surgeons discuss surgical and anaesthetic risks with patients. We investigated whether patients also wish to be informed about hospital organisational risks.
Methods
We used a cross-sectional survey. A questionnaire with three real-life scenarios of hospital organisational problems likely to increase the risk of surgery was given to 1,003 patients in neurosurgical departments of three United Kingdom (UK) teaching hospitals. The scenarios were: (1) computer failure in the operating room; (2) lack of surgical equipment; and (3) bed shortage or lack of operating capacity causing postponement of surgery. We quantified how strongly participants wish to be informed about organisational risks, whether this information alters a patient’s decision to have surgery, and the desire of patients to discuss these risks further.
Results
In total, 980 of 1,003 (97.7%) questionnaires were returned and 84.3%–88.5% of patients wished to be informed about hospital organisational risks – more women than men (odds ratio [OR] 1.6–1.8, p < 0.05). Knowledge of the hospital organisational risks would influence 69.2%–70.4% of participants’ decisions to have surgery; 74.9%–78.3% of participants wished to discuss the organisational risks with surgeons and 50.0%–60.8% with hospital managers before surgery. Some 69.4% of patients were concerned about organisational risks vs 77.1% who were concerned about surgical risks.
Conclusions
Most neurosurgery patients consider hospital organisational risks to be material. To comply with the Montgomery ruling in UK medicolegal case law, neurosurgeons and hospital managers should discuss with patients the organisational risks in addition to the surgical and anaesthetic risks during consent
Immunotherapy in Renal Cell Carcinoma
No full textRenal cell carcinoma (RCC) is a chemotherapy-resistant disease, and current molecularly targeted therapies offer limited clinical benefit but no cures. The observation that RCC is immunogenic led to immune-based strategies for the treatment of this disease. Immunotherapy with high-dose IL-2 can induce long-term, complete responses in a small percentage of patients. IFN has been used as an immune intervention as well but with much less success than IL-2. Currently IFN is used only in combination with the anti-VEGF monoclonal antibody bevacizumab. Further investigation of novel immune interventions in RCC is ongoing with promising results. Dendritic cell vaccines have been tested in single-arm clinical trials suggesting improved survival when added to standard anti-angiogenic therapy. Monoclonal antibodies against PD-1 and PD-L1, novel immune targets, have shown promising response in phase I trials. Peptide vaccines have shown efficacy in phase II trials as well. Phase III trials to test these immune interventions are currently ongoing and have the potential to bring new, effective treatment options for patients with advanced RCC
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Abstract B040: Understanding disparities in clinical trial enrollment: A study of screen failures to phase I clinical trials in a minority-serving institution in the post-COVID period
No full textAbstract Background: Phase 1 clinical trials offer a novel therapeutic option to individuals who have progressed past standard of care treatment and valuable data oncological field advancement. Previous research has shown that a significant proportion of patients referred for clinical trials do not meet eligibility criteria and are considered screen failure (SF) after consenting and even more patients referred are pre-screen failure before consenting (PSF). In addition, historically, the rate of clinical trial enrollment has been low in underrepresented minorities. These SF rates and disparities could have further increased due to COVID challenges. In this study, we aim to define the most common reasons for SF and study disparities in trial enrollment demographics in the post-COVID period. Methods: A cross-sectional sample of patients referred to the Sylvester Comprehensive Cancer Center Phase I Clinic during the pre-COVID period (11/2018-12/2019) and post-COVID period (11/2021-12/2022) was analyzed. Patients’ demographics, malignancies and SF patterns were analyzed. Reasons for SF were categorized as: cancer progression, clinical trial ineligibility, lack of applicable trial, system delays due to staffing, patient hesitancy/refusal or loss to follow-up. Chi square tests were then used to analyze the SF rate based on patient demographics. Results: During the pre-COVID period, 98 patients consented and 75 enrolled with a screen failure of 21.4%, compared to the post-COVID period when 101 patients consented and 74 enrolled with a screen failure of 27.7%. During the post-COVID period, 69 patients were PSFs, and 4 patients waitlisted and never consented. Of the PSF (n=69), 37 (55%) were female, 27 (40%) were Hispanic, 10 (15%) were Black, and 1 (1%) was Asian. The majority of PSFs were patients with thoracic cancer (45.5%), followed by GI (19%) and GYN malignancies (16.1%). The main reasons endorsed for PSFs were patients refusal/loss to follow up (35%), not consented due to system delays (20.5%), cancer progression (20.5%), trial ineligibility (17%), and lack of applicable trial (7%). When using chi square tests to analyze the prescreen failure vs. enrollment rate based on patient demographics, there was no statistically significant difference between race (p=0.19), ethnicity (p=0.45), or gender (p=0.22). Conclusion: Though the number of patients enrolled in the pre- and post-COVID period was similar, the rate of screen and prescreen failures differed. Trial design ineligibility, patient hesitancy/loss to follow up, and systemic challenges due to staff shortages contributed to SFs in the post COVID period. Staff shortages after the COVID-19 pandemic affected Phase 1 trial enrollment but was not the predominant SF reason. Studies to address clinical trial complexity and issues of patient hesitancy and withdrawal from clinical trial process are needed. The lack of demographic disparities in enrollment and SFs suggest that these system issues did not disproportionately affect any demographic group in this diverse cohort. Citation Format: Sapna A. Kedia, Rakhi Modak, Nora A. El-Abbar, Jaime R. Merchan, Estelamari Rodriguez. Understanding disparities in clinical trial enrollment: A study of screen failures to phase I clinical trials in a minority-serving institution in the post-COVID period [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B040
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Abstract 722: Epidemiological characterization of renal cell carcinoma in Hispanics: A single US center cohort study
No full textAbstract Background: Annually, there are over 400,000 new cases of renal cell carcinoma (RCC) and more than 170,000 deaths worldwide. RCC is one of the top ten more prevalent malignancies in the United States, with 76,000 new cases each year and almost 14,000 deaths. Over the past half-century, RCC has more than doubled in incidence. RCC seems to have a greater incidence among Hispanics with a nearly three-fold increase. The epidemiology of RCC in the Caucasian population has been previously studied. However, there is a knowledge gap on disparities in RCC on minority populations. Studying the epidemiology of RCC in Hispanics is integral to our community where Hispanics make up 70%. Methods: We conducted a retrospective cohort study to describe the characteristics and rates of recurrence of RCC among patients treated at Sylvester Comprehensive Cancer Center in Miami (which serves four counties in South Florida) between June 2010 to June 2022. We identified ethnicity as Hispanic/Latino (HL) or non-Hispanic/Latino (NHL). Clinical presentation was classified based on the last encounter as local RCC without recurrence, metastatic RCC after nephrectomy, and metastatic RCC at diagnosis/de novo. Results: We analyzed a total of 2049 patients aged 18 and older diagnosed with RCC, from which 1014 patients (47.90%) were identified as NHL and 933 (48.02%) as HL. A subtotal of 435 patients (22.86%) had metastatic RCC at diagnosis/de novo, from which 245 (55.60%) were NHL, and 176 (40.57%) were HL. A subtotal of 1614 patients (77.14%) were diagnosed with local RCC and underwent nephrectomy, from which 769 (45.61%) were identified as NHL and 787 (50.22%) as HL. From the NHL group that underwent nephrectomy, 223 patients (28.28%) had recurrent disease, and 546 patients (71.72%) did not. From the HL group, 176 patients (21.81%) had recurrent disease, and 611 (78.19%) did not. Overall, 409 patients had metastasis after nephrectomy, of which 176 (44.5%) were HL, and 203 (52.42%) were NHL. Conclusions: In this cohort of patients with RCC, almost 50% of patients diagnosed with metastasis were HL. NHL appeared to have more disease recurrence after nephrectomy and higher rates of metastatic disease at diagnosis compared to Hispanics. Further histopathological differences, clinical outcomes, genomic characterization, and rates of clinical trial participation between the NHL and HL cohorts will be presented at the meeting, along with comparisons between US and foreign-born HLs. Citation Format: Abner A. Murray, Jesus A. Ocejo Gallegos, Sandra Jones, Jose Noy, Rosa L. Frias, Leticia E. Campoverde, Jaime R. Merchan. Epidemiological characterization of renal cell carcinoma in Hispanics: A single US center cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 722
Abstract 5657: uPAR-mediated endothelial targeting facilitates endothelial to tumor cell transfer of oncolytic measles virus: In vitro and in vivo studies.
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A Novel Role of LMO2 in DNA Repair Control in Diffuse Large B-Cell Lymphoma
No full textLMO2 serves as one of the best prognostic markers for longer survival of diffuse large B cell lymphoma (DLBCL) patients. However, little it is known about its molecular function in normal B cells and DLBCL cells. Our study reveals a novel role for LMO2 in the control of DNA repair. We found that LMO2 inhibits the homologous recombination repair pathway, an essential mechanism for the repair of DNA double-strand breaks (DSB). The lack of activity of the homologous recombination pathway causes an accumulation of DSB in LMO2 expressing B cells, thus providing explanation for increased chemo-sensitivity of LMO2+ DLBCL tumors and the improved survival rates observed in patients with these tumors. Furthermore, based on our studies, here we propose a new treatment for LMO2-expressing DLBCL based on the observed DNA repair deficiency using Poly (ADP-ribose) polymerase (PARP) inhibitor-mediated synthetic lethality approach.</p
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The Role of PDGF AND Rac1-induced Oxidative Signaling in the Viral Oncogenesis of Kaposi's Sarcoma
No full textKaposi's sarcoma (KS), caused by the oncogenic Kaposi's sarcoma herpesvirus (KSHV), is an angiogenic tumor characterized by intense angiogenesis, inflammation and proliferation of KSHV-infected spindle cells. We describe the characterization of a mouse model of KS by transfection of a KSHV bacterial artificial chromosome (KSHVBac36) into mouse bone marrow endothelial-lineage cells which generated a cell (mECK36) that forms KS-like tumors in mice. Our results define mECK36 as a biologically sensitive animal model of KSHV-dependent KS with the following characteristics: (1) the pathological phenotype is a consequence of KSHV gene expression in normal progenitor cells subjected to in vivo growth conditions, (2) the histopathologic phenotype of the tumors resembles KS lesions, and (3) the model is suitable for analysis of vGPCR-driven tumorigenesis in the context of the whole KSHV genome. The mechanism by which vGPCR promotes tumorigenesis is not fully understood. The characterization of a Rac1 transgenic mouse model that produces KS-like lesions that highly resemble human KS has helped us to identify the potential role of Rac1, which is activated by vGPCR, in the pathogenesis of KS. The results from the RacCA transgenic mouse suggest that viral and host genes triggering Rac1 and ROS production may play an important role in KS tumorigenesis. We set out to determine how vGPCR physiologically activates Rac1 in KSHV-infected cells in the KS model mECK36. We found that KSHV oncogenesis in mECK36 is promoted by vGPCR activation of a paracrine oncogenic mechanism through PDGF-BB, which requires a Rac1- and ROS-mediated loop, leading to STAT3 transcriptional activation of c-Myc, VEGF and KSHV latent viral gene expression. We also found that the latency-associated nuclear antigen (LANA) upregulates the PDGFR in vivo, priming latently-infected cells to the PDGF signaling pathway. This oncogenic mechanism can be targeted with the antioxidant N-acetylcysteine (NAC) and FDA-approved PDGF receptor inhibitors to control KSHV-induced tumorigenesis. Our results highlight a ROS-dependent axis whereby Rac1 activating oncogenes and inflammatory signaling drive paracrine stimulation of neoplastic growth and angiogenesis in neighboring cells, defining this axis and its components as attractive anti-tumor targets in KS pathogenesis.</p
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