tbuckley/cabot-search huggingface dataset:
Abstract 5593: Inhibition of A2AR induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical and clinical studies
Authors: Stephen Willingham, Andrew Hotson, Po Ho, Carmen Choy, Kim Walter, Erik Yusko, Sharon Benzeno, Ginna Laport, Richard Miller, Ian McCaffery
Journal: Cancer Research (2017)

Abstract Adenosine signaling via A2A receptor (A2AR) on immune cells suppresses anti-tumor immunity and limits the efficacy of immunotherapy, chemotherapy, CAR-T, and vaccines. CPI-444 is a potent and selective oral A2AR antagonist. Daily treatment of mice with CPI-444 led to dose-dependent inhibition of tumor growth in multiple syngeneic tumor models. Combining CPI-444 with anti-PD-L1 treatment synergistically eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that are poorly responsive to anti-PD-1 or anti-PD-L1 monotherapy. We have initiated a Phase 1/1b clinical trial to examine safety, tolerability, biomarkers, and preliminary efficacy of CPI-444 as a single agent and in combination with the anti-PD-L1 antibody, atezolizumab, in patients with non-small cell lung, melanoma, renal, triple negative breast, and other (bladder, prostate, head and neck, colorectal) tumors. Step 1 of the trial focused on determining the optimal dose and schedule for CPI-444; Step 2 is currently evaluating the efficacy of optimal CPI-444 dosing alone and with atezolizumab. In 48 patients treated in Step 1, CPI-444 was well tolerated with 1 Grade 3 or 4 treatment related adverse events. Preliminary evidence of clinical activity was observed in patients treated with single agent CPI-444, including patients who previously failed anti-PD-1 therapy. A pCREB-based pharmacodyamic assay showed that 100 mg, BID dose of CPI-444 resulted in a complete, sustained inhibition of A2AR on circulating immune cells. CPI-444 treatment alone or in combination with atezolizumab resulted in increased frequency of circulating CD8+PD-1+ cells and memory/effector subsets of CD4+ and CD8+ T cells. Substantial changes in TCR repertoire (Morisita Index &amp;lt;0.9) were observed in both anti-PD-1 native and refractory patients and correlated to patient responses. CD73 expression, CD8+ infiltration, TREG distribution, and gene expression signatures are currently being evaluated in serial tumor biopsy specimens and will be presented. In total, this shows that CPI-444 is well tolerated in cancer patients, exhibits functional inhibition of adenosine signaling, and treatment is associated with activation of anti-tumor immunity and clinical activity. Citation Format: Stephen Willingham, Andrew Hotson, Po Ho, Carmen Choy, Kim Walter, Erik Yusko, Sharon Benzeno, Ginna Laport, Richard Miller, Ian McCaffery. Inhibition of A2AR induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical and clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5593. doi:10.1158/1538-7445.AM2017-5593
Abstract 5186: Vemurafenib selectively radiosensitizes BRAF V600E mutant papillary and anaplastic thyroid carcinoma cells
Authors: Ryan N. Robb, Linlin Yang, Terence Williams
Journal: Cancer Research (2017)

Abstract BRAF activating mutations act as oncogenic drivers and are highly prevalent in thyroid cancer, occurring in about 60% of papillary thyroid cancer (PTC) as well as 30-40% anaplastic thyroid cancer (ATC). MAPK signaling and treatment resistance is driven by BRAF mutations in thyroid cancer. Among the most common of these mutations is BRAFV600E, which can be selectively inhibited by vemurafenib. Using a panel of PTC and ATC cell lines we assessed how the presence/absence of BRAFV600E impacts radiation sensitivity. We used radiation clonogenics, comet assays, nuclear foci formation, immunoblotting, and mouse xenografts models to determine the effect of vemurafenib on PTC and ATC cells. Analysis of radiation clonogenics implicated higher radioresistance in cell lines containing the BRAFV600E mutation as compared to wild-type BRAF. Additionally, forced expression of BRAFV600E in a wild-type thyroid cancer cell line induced radioresistance. Vemurafenib inhibited MAPK signaling in V600E mutant cell lines, but showed no effect in BRAF wild-type cell lines. Vemurafenib pretreatment selectively radiosensitized BRAFV600E mutants in vitro, as assessed by radiation clonogenic assays. Comet assays revealed impairment of DNA repair in BRAFV600E lines when treated with vemurafenib and radiation. Additionally, γ-H2A.x westerns and nuclear foci staining indicated that vemurafenib pretreatment decreases the tumor cell’s ability to repair DNA double-strand breaks (DSB) in BRAFV600E cell lines. Vemurafenib also appeared to alter the kinetics of formation and resolution of 53BP1 and Rad51 nuclear foci in these cell lines. Evaluation of DSB functional repair using GFP reporter constructs, suggests that BRAFV600E induces NHEJ repair, which can be attenuated by vemurafenib treatment. Finally, vemurafenib effectively increases radiosensitivity of BRAF V600E tumors in vivo. From our results, BRAF activating mutation appears to be associated with radioresistance. Vemurafenib selectively radiosensitizes both PTC and ATC cells through inhibition of DNA repair mechanisms. Combining vemurafenib and radiation may improve therapeutic control for BRAFV600E mutant thyroid cancers. Citation Format: Ryan N. Robb, Linlin Yang, Terence Williams. Vemurafenib selectively radiosensitizes BRAF V600E mutant papillary and anaplastic thyroid carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5186. doi:10.1158/1538-7445.AM2017-5186
Abstract 5163: Characterization of NMS-E194, a selective and potent PERK inhibitor with efficacy in the KMS-11 multiple myeloma
Authors: Claudia Perrera, Maurizio Pulici, Davide Carenzi, Ilaria Motto, Marina Fasolini, Elena Casale, Stefania Re Depaolini, Simona Rizzi, Daniela Asa, Fulvia Roletto, Simona Bindi, Daniele Casero, Patrizia Banfi, Elena Ardini, Nadia Amboldi, Dario Ballinari, Fabio Gasparri, Sabrina Cribioli, Laura Mancini, Marina Ciomei, Daniele Donati, Eduard Felder, Arturo Galvani, Antonella Isacchi, Barbara Valsasina
Journal: Cancer Research (2017)

Abstract PERK (PKR-like endoplasmic reticulum kinase) is a serine-threonine kinase associated to endoplasmic reticulum membrane. Together with ATF6 and IRE1, PERK is a key effector of the Unfolded Protein Response (UPR), a network of signaling pathways that ensures protein homeostasis in the endoplasmic reticulum. Multiple Myeloma (MM) and other protein-secreting tumors are highly dependent on UPR for survival, and inhibition of PERK may be an effective strategy to inhibit growth of these tumors. Here we describe the in vitro and in vivo properties of NMS-E194, a novel potent and selective ATP-competitive PERK inhibitor belonging to the arylsulfonamide chemical class. NMS-E194 inhibits PERK kinase with a Ki of ca 1.5 nM in biochemical assay and possesses high selectivity towards a panel of 54 kinases. When tested in cell proliferation assays, NMS-E194 is preferentially active on multiple myeloma (MM) and diffuse large B cell lymphoma cell lines. In mechanism of action studies, NMS-E194 shows a bi-phasic behaviour: at low nanomolar doses it activates PERK, causing ATF4 accumulation, while at &amp;gt;200 nM it inhibits PERK and downstream pathway, inducing apoptosis. NMS-E194 possesses a favourable in vitro ADME profile and has promising PK properties in the mouse. NMS-E194 demonstrated strong anti-tumor activity following oral administration at 25 mg/kg daily to mice harbouring luciferized KMS-11 cells in a disseminated growth model of MM, with no overt toxicity. Overall, the data available so far warrant further development of NMS-E194 and support PERK inhibition as a novel therapeutic approach in MM and other PERK-dependent tumors. Citation Format: Claudia Perrera, Maurizio Pulici, Davide Carenzi, Ilaria Motto, Marina Fasolini, Elena Casale, Stefania Re Depaolini, Simona Rizzi, Daniela Asa, Fulvia Roletto, Simona Bindi, Daniele Casero, Patrizia Banfi, Elena Ardini, Nadia Amboldi, Dario Ballinari, Fabio Gasparri, Sabrina Cribioli, Laura Mancini, Marina Ciomei, Daniele Donati, Eduard Felder, Arturo Galvani, Antonella Isacchi, Barbara Valsasina. Characterization of NMS-E194, a selective and potent PERK inhibitor with efficacy in the KMS-11 multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5163. doi:10.1158/1538-7445.AM2017-5163
Clinical impact of multi-gene panel testing for hereditary breast and ovarian cancer risk assessment.
Authors: Leif W. Ellisen, Allison W. Kurian, Andrea J Desmond, Meredith Mills, Stephen E Lincoln, Kristen M Shannon, Michele Gabree, Nadine M. Tung, James M. Ford
Journal: Journal of Clinical Oncology (2015)

1513 Background: Genetic testing for hereditary breast and ovarian cancer is evolving with the recent introduction of multi-gene panels, although the clinical impact of such panels is as yet poorly defined. For patients without BRCA1/2 mutations management is guided by personal and family history, although additional (non-BRCA) mutations can contribute additional information regarding risk for both the patient and their family members. It is unknown how often finding such mutations, including those that lack gene-specific guidelines, will potentially alter clinical management. Methods: We used similar 25 or 29 gene panels to test 1112 patients enrolled prospectively as appropriate candidates for HBOC evaluation at three academic medical centers. We applied uniform criteria to analyze the clinical impact of the non-BRCA1/2 mutations observed in these patients and also in comparable patients at these centers. Primary outcome measures included the frequency and types of potential management changes based on each patient’s gene-associated cancer risks given personal/family history and established risk-based practice standards. Results: The prevalence of BRCA (9.0%, CI 7.1-11.3%) and non-BRCA (3.9%, CI 2.7-5.6%) mutations was in line with previous studies and suggests that this was a representative population. The most common non-BRCA findings involved known breast/ovarian cancer genes (PALB2, ATM, and CHEK2) and Lynch syndrome genes. Among 61 patients in all groups with non-BRCA findings, the majority would result in consideration of additional disease-specific screening and/or prevention measures for the patient (56%, 34/61) or mutation-positive first-degree relatives (76%, 42/55). Conclusions: In appropriately-referred patients, multi-gene panel testing yields clinically relevant findings with potential management impact for substantially more patients than does BRCA1/2 testing alone. Thus, this approach may improve care for many mutation-affected individuals in the short term, and in the long term should lead to the development of additional evidence-based guidelines for at-risk individuals.
Abstract 1412: High EGFR somatic mutation frequency targeting the TK domain in colorectal cancer patients with microsatellite instability (MSI)
Authors: Safoora Deihimi, Michael Slifker, Eric A. Ross, Wafik S. El-Deiry
Journal: Cancer Research (2017)

Abstract CRCs arise through genetic changes that impact various driver genes and in some tumors increased mutation rate in microsatellite unstable tumors. The hypermutable phenotype associated with microsatellite instability (MSI) results from loss of the mismatch repair system (MMR) activity. MSI is detected in 15% of all CRCs, and such tumors have a better prognosis and different chemotherapeutic outcome patterns, including high clinical benefit from immune checkpoint therapy or relative resistance to 5-FU as compared to microsatellite stable (MSS) tumors. The epidermal growth factor receptor (EGFR) signaling pathway plays an essential role in carcinogenesis of CRCs and is known to be overexpressed in MSI CRCs while highly mutated in Lung cancer. We analyzed the mutation frequency of deregulated pathways including EGFR and its downstream genes KRAS and BRAF in CRCs. We found a significantly elevated EGFR mutation frequency in CRC MSI-H subtype (45.5% vs. 6.5% in MSS CRCs, p&amp;lt;0.0000001). Although KRAS and NRAS are mutated with high frequency in both MSI-H and MSS groups, BRAF corresponding to RTK-RAS pathways is more altered in MSI-H than MSS CRCs (32.67% vs 13.10%; p=0.001), consistent with the known association between MSI-H CRCs and BRAF mutations. We hypothesized that there might be a mutation pattern in EGFR in CRC subtypes that provide a rationale for EGFR-targeted therapy for a subtype of CRC. Of 1104 profiled CRCs in the COSMIC v73 database, somatic EGFR mutations were mapped for 101 MSI-High versus 916 MSS CRCs. EGFR mutations mapped on the protein structure revealed that mutations are mainly targeting tyrosine kinase (TK) domain while the extracellular domain remained mostly wild-type with potential for targeting by anti-EGFR monoclonal antibodies. It is known that downstream genes such as KRAS as well as expression levels of EGFR ligands can affect the sensitivity of CRCs to anti-EGFR therapy. We didn’t detect any difference in mRNA expression level between MSI-H and MSS group but our analysis is indicative of the presence of G12D mutations in a high proportion of KRAS-mutated MSS CRCs, therefore resistance to anti-EGFR antibodies such as cetuximab would be expected. However, EGFR tyrosine kinase inhibitors such as erlotinib and gefitinib could be considered for further testing in patients with MSI-H tumors that have a lower frequency of G12D KRAS mutations and may have mutant EGFR. Citation Format: Safoora Deihimi, Michael Slifker, Eric A. Ross, Wafik S. El-Deiry. High EGFR somatic mutation frequency targeting the TK domain in colorectal cancer patients with microsatellite instability (MSI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1412. doi:10.1158/1538-7445.AM2017-1412
Cancer Screening in Li-Fraumeni Syndrome
Authors: Peter H. Asdahl, Rohit P. Ojha, Henrik Hasle
Journal: JAMA Oncology (2017)

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Abstract 1357: The small GTPase Arf6 potentiates melanoma metastasis by activating Akt
Authors: Lehi Acosta, Aaron Rogers, Jae H. Yoo, Shannon J. Odelberg, Dean Y. Li, Sheri Holmen, Allie H. Grossmann
Journal: Cancer Research (2017)

Abstract Arf6 is a member of the Ras-superfamily of small GTPases and controls membrane trafficking and cytoskeletal remodeling, functioning mainly in endocytosis pathways at the cell periphery. Arf6 is activated by various extracellular signals and oncogenic events and has been shown to promote cell migration and pro-invasive phenotype in human cancer cells. Small molecule inhibition of ARF6 reduces spontaneous metastasis in xenograft models of human cutaneous melanoma, suggesting that ARF6 is necessary for disease progression. Using a genetically-engineered mouse model of BRAF-mutant melanoma, we determined whether activation of Arf6 is sufficient to induce spontaneous metastasis in vivo. For melanocyte-specific primary tumor induction, Cre recombinase was delivered via local injection of RCAS virus into DCT-TVA;Cdkn2alox/lox;BRAFV600E mice. In the experimental mice, a constitutively active mutant form of Arf6 (Q67L) was virally delivered with Cre. In this study, we observed a significant increase in spontaneous metastatic disease burden in Arf6 Q67L mice. Likewise, tail vein injection of melanoma cell lines derived from Arf6 Q67L tumors consistently show a diffuse pattern of pulmonary metastasis compared to controls that show rare, microscopic metastasis. Recently, it has been demonstrated that activation of Akt, but not Pten loss, leads to an aggressive phenotype in melanoma that includes the acquisition of brain metastases. Immunohistochemical analysis of phospho-Akt revealed that Arf6 Q67L is sufficient to induce Akt activation in tumors. In addition, ARF6 is necessary for AKT activation in human melanoma lines. We did not observe brain metastasis in DCT-TVA;Cdkn2alox/lox;BRAFV600E + Arf6 Q67L mice. When we added Ptenlox/lox allele to this genetic background, however, we observed microscopic brain metastases at a low frequency, suggesting that the combination of Pten loss and Arf6 activation reaches a threshold level of Akt activation that is sufficient to cause brain metastasis. Taken together our data indicate that activation of Arf6 is sufficient to potentiate melanoma metastasis, consistent with the proinvasive cellular phenotype attributed to Arf6. In addition, our data suggests a novel signaling mechanism by which Arf6, a small GTPase involved in trafficking, is somehow involved in Akt activation and that this step may be important for the acquisition of metastatic capacity. Citation Format: Lehi Acosta, Aaron Rogers, Jae H. Yoo, Shannon J. Odelberg, Dean Y. Li, Sheri Holmen, Allie H. Grossmann. The small GTPase Arf6 potentiates melanoma metastasis by activating Akt [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1357. doi:10.1158/1538-7445.AM2017-1357
Abstract LB-203: VXL100, a MUC1 signal peptide based immunotherapy, acts through a neoantigen-like mechanism, and shows promising effects in hematological cancers
Authors: Limor Chen, Riva Kovjazin, Michael Shapira
Journal: Cancer Research (2017)

Abstract VXL100 (ImMucin®), a 21mer peptide, pan-HLA vaccine derived from the MUC1 signal peptide (SP) domain, has been shown to be safe and to elicit a robust and specific T and B-cell responses in stable and progressive multiple myeloma patients in a phase I/II clinical trial. It is now becoming recognized that the advantages of using the signal peptide domain for immunization stem from its unique B and T cells epitope restriction density and TAP independent presentation. Additionally, the low avidity of signal peptides as antigens, is believed to result in escaping negative selection in the thymus during development, and preservation of active clones in the peripheral blood. This may allow signal peptides to be presented as true neoantigens during tumor development and generate a robust immune response. To prove the neoantigenic properties of MUC1 SP, we have recently tested endogenous levels of specific anti-VXL100 T-cells by staining for VXL100-specific or control multimers. We also performed proliferation assays for patient TIL and normal donors PBMCs using cells stimulated with VXL100 or other MUC1 antigenic control peptides. VXL100 specific T-cell were found in 100% of patients (1.3-6%), VS. 0% in normal donors. We have found a direct correlation between the MUC1 signal peptide expression levels on tumor cells and levels of endogenous VXL100 specific T-cells. Positive signals were observed for multimers of other MUC1 peptides as well, but these were also seen in normal donors, suggesting a non-specific binding. Moreover, we were able to show that VXL100 specific exhausted CD8 cells exist at a non-significant levels as compared to the total exhausted CD8. When stimulated in-vitro with VXL100, PBMCs from 70% of naive normal donors and 94% of cancer patients showed a strong proliferative response (average of 8.9% and 16.5% proliferating cells, respectively). When stimulated with control peptides 0.5% - 5.2% of patients and 0 - 13% of donors showed positive proliferation response. Conclusions: VXL100, a novel immunotherapy agent shows the capacity to elicit a specific and robust T-cell response in healthy individuals and hematological cancer patients. These features suggest that MUC1 SP is a native sequence functioning as a cancer neoantigen and preserved through normal and tumor development. It presents an attractive opportunity for the development of an effective cancer immunotherapy. Citation Format: Limor Chen, Riva Kovjazin, Michael Shapira. VXL100, a MUC1 signal peptide based immunotherapy, acts through a neoantigen-like mechanism, and shows promising effects in hematological cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-203. doi:10.1158/1538-7445.AM2017-LB-203