bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1063: Benefit from combination cancer therapy arising from patient-to-patient variability rather than additive or synergistic drug action
Authors: Palmer Adam C. , Sorger Peter K.
Published: July 2017

Combination cancer therapy is an important means to increase rates and durability of drug response. Superior responses to combination therapies are commonly interpreted as evidence that individual tumors respond more strongly to a combination than to a monotherapy, and combinations are often developed based on pre-clinical observations of drug additivity or synergy. Here we explore an alternative hypothesis, namely that combination therapy can confer benefit simply by providing multiple chances of an above-average response to monotherapy.

The benefit conferred by two-drug combination therapy in human clinical trials and PDX animals was compared with a model of independent drug action postulating that net response in each patient equals the better of two potential responses to drugs given individually with no benefit from the second agent. Data were derived from clinical trials of drug combinations in melanoma, ovarian, colorectal, pancreatic, and breast cancers treated with immunotherapies, chemotherapies and inhibitors of kinases, growth factor receptors, angiogenesis, and DNA repair enzymes; as well as analysis of 4,500 drug response measurements in patient-derived tumor xenografts, and a first-principles model of tumor kinetics and variability in drug response.

A majority of approved combination cancer therapies analyzed confer benefits consistent with independent drug action. This benefit arises from high inter-subject variability, which can be assessed from clinical trials, and low correlation in responsiveness to different drugs, assessed from PDX studies. In a minority of cases responses exceed this expectation, sometimes dramatically, and are likely to represent true drug interaction. Therefore, independent drug action, without any assumption about additive or synergistic effects, provides a sufficient and more parsimonious explanation for the superiority of many clinically approved combination cancer therapies and changes how such data are interpreted mechanistically. Optimization of independent action also provides an alternative means for designing new drug combinations.

Citation Format: Adam C. Palmer, Peter K. Sorger. Benefit from combination cancer therapy arising from patient-to-patient variability rather than additive or synergistic drug action [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 1063. doi:10.1158/1538-7445.AM2017-1063
Abstract 107: Mechanism of anticancer activity of BPS-001 (lyophilized leech saliva extract)
Authors: Ammar Amr , Guns Emma , Kucuk Omer , Abdualkader Abdualrahman , Alaama Mohamed , Uddin A.B.M. Helal , Ghawi Abbas , Hassona Mohamed
Published: July 2017

Recent studies, investigating the composition and therapeutic potential of leech saliva have identified many peptides and proteins with multiple therapeutic properties including anti-thrombotic, antimicrobial and anti-metastatic. In vitro anti-cancer effects were shown in breast, prostate and lung cells lines. In vivo anticancer activity of the extract was shown in multiple breast and prostate cancer xenografts studied by our lab. In our previous studies, BPS-001 was non-toxic and demonstrated various activities including pro-apoptotic properties, inhibition of cellular adhesion, angiogenesis and downregulation of AR expression. To investigate the affected pathways, mechanistic studies were carried out using in vivo and in vitro treated samples. Protein expression in samples was determined by Western blotting of in vitro and in vivo samples. AR expression was measured using an eGFP reporter assay in LNCaP cells, with PSA also measured in the media using cobas e 411 analyzer. BPS-001 inhibited Proteinase Activated Receptor 1 (PAR-1) which is responsible for hormone like cellular signals in different cancer cells including those of the breast and prostate. Moreover, in LNCaP cells AR activation and PSA expression were significantly inhibited after treatment with BPS-001. Inhibition of PI3K and PLCG2 were also observed. It has been found that BPS-001 modulates a plethora of pathways which makes it a very promising candidate for treatment of cancer with an important advantage of low toxicity and potential resistance.

Citation Format: Amr Ammar, Emma Guns, Omer Kucuk, Abdualrahman Abdualkader, Mohamed Alaama, A.B.M. Helal Uddin, Abbas Ghawi, Mohamed Hassona. Mechanism of anticancer activity of BPS-001 (lyophilized leech saliva extract) [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 107. doi:10.1158/1538-7445.AM2017-107
Abstract 1084: Combination of eribulin and AURKA inhibitor prevents metastatic colonization and eradicates established metastases in breast cancer
Authors: Pugacheva Elena N. , Kozyreva Varvara , Kiseleva Anna , Ice Ryan , Jones Brandon , Loskutov Yuriy
Published: July 2017

The majority of cancer-related deaths (90%) are happened due to metastasis from the primary tumor site to distant organs. MLN8237 is a small, highly selective molecule inhibitor of Aurora A kinase (AURKA), which results in disruption of the mitotic spindle, chromosome segregation collapse, and inhibition of cell proliferation. Numerous studies have showed that levels of AURKA are elevated in many types of cancer, including breast cancer. Our previous studies indicated that MLN8237 is extremely potent against pulmonary metastasis, but not the primary tumor in orthotropic xenograft model. To further enhance MLN8237 based regiment, its combination with other therapeutic compounds can be used. As a potential partner we chose eribulin - fully synthetic macrocyclic analogue of the marine natural product halichondrin B. Eribulin belong to the class of non-taxane microtubule destabilizing molecules, currently used in clinic to treat taxol resistant metastatic breast cancer. In present study we have investigated the effect of MLN8237 and eribulin against breast cancer in vivo and in vitro. The results showed that combination of drugs possess a synergistic effect on both primary tumor and metastases, through inducing cytotoxic autophagy and apoptosis. This data clearly indicate great potential behind the MLN8237 based therapies and introduce a new hope for the eradication of metastatic breast cancer.

Citation Format: Elena N. Pugacheva, Varvara Kozyreva, Anna Kiseleva, Ryan Ice, Brandon Jones, Yuriy Loskutov. Combination of eribulin and AURKA inhibitor prevents metastatic colonization and eradicates established metastases in breast cancer [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 1084. doi:10.1158/1538-7445.AM2017-1084
Abstract 1092: PF562271, a Pyk2 inhibitor, reduces glioma tumor growth and invasion in C57Bl6-Gl261 mouse glioma model
Authors: Ortiz-Rivera Jescelica , Rolón-Reyes Kimberleve , Albors Alejandro , Cubano Luis , Kucheryavykh Lilia
Published: July 2017

Glioblastoma is an extraordinarily aggressive type of brain cancer due to its invasive and proliferative nature. The tumor microenvironment, with microglia as a critical player, has an important role in tumor progression. Microglia infiltrate majority of gliomas and release factors, which favor tumor growth and invasion. Previously we demonstrated that microglia residing within the tumor stimulate glioma cell invasion through the proline rich tyrosine kinase 2 (Pyk2) signaling cascade. We hypothesize that the use of pharmacological inhibitors of Pyk2 together with currently applied chemotherapy can significantly reduce invasiveness of glioblastoma tumor and improve the outcome of the treatment. Using C57Bl/6-Gl261 mouse glioma implantation model we investigated the effect of the combined treatment for glioblastoma with temozolomide (TMZ, 50 mg/kg, once/day, orally) together with a Pyk2 inhibitor PF562271 (twice/daily, 25 mg/kg, orally) vs. TMZ monotherapy. Treatment was provided during 14 days, beginning the 5th day after glioma implantation. For the assessment of the effectiveness of treatment animals’ survival, tumor size, and invasion area were evaluated. Western blot were used for the evaluation of the level of Pyk2 phosphorylation in tumor cells. For the purification of glioma cells from total tumor tissue Percol gradients were used. The study revealed that treatment with PF562271 reduced invasion of glioma cells at the tumor edge, while TMZ reduced the tumor growth. Combined treatment showed significantly more prominent effect on reduction of tumors growth compared to TMZ monotherapy and additionally reduced invasiveness of tumors similar to PF562271 monotherapy. In both PF562271 monotherapy and combined treatments the downregulation of Pyk2 phosphorylation in glioma cells has been recorded. Survival analysis demonstrated a significance increase of survival of animals received combined treatment compare to TMZ monotherapy. In conclusion, we can state that combined treatment with TMZ together with PF562271 reduced Pyk2-related tumor growth and invasiveness and increased animal survival. This research was made possible by NIH grant numbers: 1SC2GM102040, G12MD007583, R25GM110513, Puerto Rico Science, Technology, and Research Trust grant number 2016-00157, and US Department of Education Grant number P031S130068.

Citation Format: Jescelica Ortiz-Rivera, Kimberleve Rolón-Reyes, Alejandro Albors, Luis Cubano, Lilia Kucheryavykh. PF562271, a Pyk2 inhibitor, reduces glioma tumor growth and invasion in C57Bl6-Gl261 mouse glioma model [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 1092. doi:10.1158/1538-7445.AM2017-1092
Abstract 1094: Combining the pan-FGFR inhibitor AZD4547 with radiation in lung and head and neck squamous cell carcinoma
Authors: Baschnagel Andrew M. , Li Chunrong , Morgan Alecia M. , Brennan Sean R. , Russo Kalley A. , Harari Paul M.
Published: July 2017

The fibroblast growth factor receptors (FGFR1, FGR2, FRG3, FGR4) are frequently altered or overexpressed in both lung and head and neck squamous cell carcinomas (SCC). Amplification of FGFR1 has been reported to be as high as 22% in lung SCC and 17% in head and neck SCC (HNSCC). FGFRs have been identified as a potential therapeutic target in lung and head and neck cancers. In addition, FGFRs activate multiple pathways involved in the radiation response including RAS/RAF/MAPK, PI3K/AKT and STAT. AZD4547 is a potent and selective tyrosine kinase inhibitor of the FGFR family and is currently being investigated in clinical trials. Since a substantial portion of lung cancer and HNSCC patients are treated with radiotherapy, we examined the anti-tumor effects of AZD4547 in combination with radiation in both lung and head and neck cancer model systems. FGFR protein and RNA expression and cell proliferation with AZD4547 were evaluated in 8 lung and 8 head and neck cancer cell lines. Clonogenic survival assays were performed on 4 lung and 4 head and neck cancer cell lines and xenograft experiments were performed on one HNSCC cell line. These cell lines demonstrated varying levels of FGFR1, 2 and 3 protein and RNA expression. The half maximal inhibitory concentration (IC50) of AZD4547 in these cell lines ranged from 0.05 to 128 uM. Sensitivity to AZD4547 did not correlate directly with protein or RNA expression. In vitro clonogenic survival assays showed limited effects of combining AZD4547 with radiation. However, significant tumor growth delay was observed with the combination of radiation and AZD4547 compared to radiation or drug alone in the SCC1483 FGFR2 expressing HNSCC xenograft model. These findings suggest that AZD4547 can augment the response of radiation in an in vivo model system. Further studies are underway to test these findings in additional cell lines including FGFR dependent amplified cancer cell lines.

Citation Format: Andrew M. Baschnagel, Chunrong Li, Alecia M. Morgan, Sean R. Brennan, Kalley A. Russo, Paul M. Harari. Combining the pan-FGFR inhibitor AZD4547 with radiation in lung and head and neck squamous cell carcinoma [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 1094. doi:10.1158/1538-7445.AM2017-1094
Abstract 1097: Enhancing the efficacy of Temozolomide with Biochanin A: Mechanistic and metabolic effects
Authors: Desai Vilas , Jain Aditi , Perepelyuk Maryna , Chhun Annie , Farrell Christopher , Lai James C. K. , Bhushan Alok
Published: July 2017

Enhancing the efficacy of Temozolomide with Biochanin A: Mechanistic and Metabolic effects

Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM is characterized by aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. Furthermore, the current standard therapy of surgical resection followed by radiotherapy and chemotherapy with Temozolomide is not very effective. The inefficacy of the currently available chemotherapeutic agents for GBM can be attributed to the challenges of drug delivery to the tumor. Our laboratory has previously reported the anticancer potential of isoflavones like Biochanin A against oral, pancreatic, breast and brain cancers. In this study, we tested our hypothesis that, Biochanin A sensitizes the GBM cells to Temozolomide, thereby increasing its efficacy in combination treatment. We used the MTT assay to determine the effects of Biochanin A alone and in combination with Temozolomide on survival of U-87 MG cells. Furthermore, two different nanoformulations of Single Walled Carbon Nanotubes (SWCNTs) functionalized with Biochanin A and Atorvastatin and SWCNTs functionalized with Temozolomide were synthesized and their effects on cell viability of U-87 MG glioblastoma cells tested. The cell viability results indicate a decrease in cell proliferation with the combination treatment as compared to the individual drug treatment. Similarly, the flow cytometry analysis showed an increased induction of apoptosis with combination treatment as compared to the drugs alone. Western-blot analysis and Immunofluorescence imaging methods were used to elucidate some of the cell survival/proliferation mechanisms involving EGFR, p-AKT, MMP-2, MT-MMP1. The effects of the drugs on U-87 MG cell metabolism (parameters like ECAR & OCR) studied using Seahorse XFp analyser, suggest an increase in the mitochondrial respiration. Our results provide support for our hypothesis and the data shows that it may have implications in increasing the efficacy of the conventional treatments for GBM. These results will potentially aid in designing new therapies that can improve the outcome of GBM.

Citation Format: Vilas Desai, Aditi Jain, Maryna Perepelyuk, Annie Chhun, Christopher Farrell, James C. K. Lai, Alok Bhushan. Enhancing the efficacy of Temozolomide with Biochanin A: Mechanistic and metabolic effects [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 1097. doi:10.1158/1538-7445.AM2017-1097
Abstract 11: The oncolytic peptide LTX-315 enhances T cell clonality and induces synergy with chemotherapy
Authors: Camilio Ketil André , Wang Meng Yu , Nestvold Janne , Mælandsmo Gunhild , Sveinbjørnsson Baldur , Rekdal Øystein
Published: July 2017

LTX-315, a novel oncolytic peptide is effective against both drug-resistant and drug-sensitive cancer cells with lower toxicity towards normal cells. Intratumoral treatment with LTX-315 results in growth inhibition, complete regression and long lasting tumor-specific immune responses.

The oncolytic effect of LTX-315 involves perturbation of the plasma membrane and distortion of intracellular organelles including the mitochondria with subsequent release of Damage-Associated Molecular Pattern molecules (DAMPs) such as ATP, cytochrome c and HMGB1. LTX-315 effectively induces necrosis within the tumor followed by the release of tumor antigens as demonstrated by a greater increase in tumor infiltrating CD8+ T cells, expansion of T cell clonality, and number of clones within the tumor microenvironment.

LTX-315`s ability to modify the tumor microenvironment makes it ideal as a combination partner for other cancer therapies, including chemotherapy and immune checkpoint inhibitors.

In preclinical tumor models, combination of LTX-315 and chemotherapeutic agents such as cyclophosphamide and doxorubicin demonstrates significant synergy.

Citation Format: Ketil André Camilio, Meng Yu Wang, Janne Nestvold, Gunhild Mælandsmo, Baldur Sveinbjørnsson, Øystein Rekdal. The oncolytic peptide LTX-315 enhances T cell clonality and induces synergy with chemotherapy [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 11. doi:10.1158/1538-7445.AM2017-11
Abstract 110: Quantitative high throughput screening as a tool to identify novel therapies in bladder cancer
Authors: Railkar Reema , Sanford Thomas , Krane L. Spencer , Agarwal Piyush K.
Published: July 2017

Introduction: Bladder cancer (CaB) is the 4th most common cancer among men in the US. It is the most expensive malignancies to treat from diagnosis to death. No new pharmacological agents have been approved for treatment of bladder cancer since the approval of BCG in 1990. Thus, there is an urgent need for development of new treatment therapies. Quantitative high throughput screening (qHTS) of representative cancer lines with oncology drugs may identify new treatments or re-purpose already existing therapies for different disease. We utilized this technique to identify new therapies in two primary bladder lines (T24 and UMUC3) and their metastatic lines (T24T, SLT3 and FL3 of T24 and LUL-2 for UMUC3).

Methods: We screened 7 bladder cancer cell lines against 1,912 oncology drugs using a 48 hour cell proliferation assay with an ATP−based readout (CellTiterGlo) to determine activity and potency of compounds in a dose response manner. One of the candidate drugs inhibitory in all cell lines tested is flavopiridol, a pan CDK inhibitor. We further characterized the mechanism of action and in vivo effects of flavopiridol using various cell based assays and mouse xenograft studies.

Results: The initial screen identified 95 compounds active in 7 cell lines. The top 50 compounds were further analyzed for molecular size of >200 g/mol and TPSA<90. This identified mitomycin C and 8 novel compounds. Further testing revealed Flavopiridol to be most consistent with qHTS data having IC50 of 100-300nM in all the cell lines tested. Flavopiridol induces G2/M arrest; however, very little apoptosis was seen suggesting cytostatic rather than cytotoxic mechanism of flavopiridol action. Flavopiridol showed dose dependent inhibition of migration, invasion and colony formation in CaB cell lines tested. Xenograft studies in rapidly growing UMUC-3 cells showed slowing of tumor growth but not complete reduction indicating cytostatic mechanism of flavopiridol. However, in slow growing cells, 5637, 5/8 treated mice showed complete tumor reduction.

Conclusions: qHTS can identify novel compounds. Flavopiridol seems to be a very effective inhibitor both in vitro and in vivo. Physical properties of Flavopiridol are most suited for intravesical use which may lead to it being an effective inhibitor of CaB in the bladder at higher doses without any/few systemic toxicities. Studies are underway to elucidate the use of flavopiridol as a single intravesical agent.

Citation Format: Reema Railkar, Thomas Sanford, L. Spencer Krane, Piyush K. Agarwal. Quantitative high throughput screening as a tool to identify novel therapies in bladder cancer [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 110. doi:10.1158/1538-7445.AM2017-110
Abstract 1102: Anti-tumor effects of imipridone ONC201 in combination with anti-angiogenic agents significantly impact on colorectal cancer growth in vivo
Authors: Wagner Jessica , El-Deiry Wafik
Published: July 2017

Small molecule imipridone ONC201 is an investigational anti-tumor agent with a wide therapeutic index and broad-spectrum efficacy in vivo. ONC201 upregulates intratumoral TRAIL expression and the integrated stress response pathway. A Phase I clinical trial using ONC201 as therapy in advanced cancer patients has been completed and the drug has progressed into several Phase II trials in multiple cancer types. Colorectal cancer (CRC) remains one of the leading causes of cancer worldwide and metastatic disease continues to have a poor prognosis. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents. Bevacizumab is a humanized monoclonal antibody that targets VEGF and is an FDA-approved treatment for advanced CRC patients, in addition to other tumor types. We are investigating the potential combination of VEGF inhibitors such as bevacizumab and ONC201 in both CRC xenograft and patient-derived xenograft (PDX) studies. Our results demonstrate significant tumor regression and occasional tumor ablation in human xenografts with the combination of ONC201 with bevacizumab, and in syngeneic MC-38 colorectal cancer xenografts using a murine VEGF-A inhibitor. Non-invasive angiogenesis imaging demonstrated the impact of this combination on decreasing tumor growth and tumor metastasis. With the use of both a murine VEGF inhibitor in syngeneic models, and bevacuzimab in human cell line-derived xenografts, we have demonstrated that combining anti-angiogenic therapies with ONC201 could enhance antitumor efficacy. Thus, ONC201 in combination with anti-angiogenic therapies such as bevacizumab represents a promising combinatorial approach that may be exploited in the clinic for the treatment of CRC.

Citation Format: Jessica Wagner, Wafik El-Deiry. Anti-tumor effects of imipridone ONC201 in combination with anti-angiogenic agents significantly impact on colorectal cancer growth in vivo [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 1102. doi:10.1158/1538-7445.AM2017-1102
Abstract 1113: Inhibition of DNA repair by NR1D1 enhances chemosensitivity of breast cancer cells
Authors: Ka Na-Lee , Na Tae-Young , Na Hyelin , Lee Mi-Ock
Published: July 2017

Most chemotherapeutic agents exert cytotoxic effects by inducing excessive DNA lesions in cancer cells. Therefore, regulating DNA repair networks is a critical factor that determines sensitivity of cancer cells to chemotherapeutic drugs. In this study, we identified the role of nuclear receptor NR1D1 in DNA repair, which enhanced chemosensitivity in breast cancer cells. NR1D1 inhibited recruitment of the DNA repair complex to damaged DNA sites, thereby impaired proper DNA repair upon doxorubicin treatment in breast cancer cells. Interaction with Poly(ADP-ribose) polymerase-1 and subsequent PARylation were critical steps that allow NR1D1 to translocate to DNA double-strand breaks. In agreement, depletion of NR1D1 in MCF-7 cells resulted in resistance to a chemotherapeutic drug, doxorubicin, in both in vitro and in vivo experiments. Further, NR1D1 expression level was correlated positively with clinical outcomes in breast cancer patients who received chemotherapy. Thus, NR1D1 and its ligands may provide better therapeutic options that could enhance the outcomes of adjuvant chemotherapy in breast cancer patients.

Citation Format: Na-Lee Ka, Tae-Young Na, Hyelin Na, Mi-Ock Lee. Inhibition of DNA repair by NR1D1 enhances chemosensitivity of breast cancer 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 1113. doi:10.1158/1538-7445.AM2017-1113
Abstract 1119: Targeting tankyrases as a therapeutic strategy for triple-negative breast cancer
Authors: Mathew Maya , Campo Loredana , Kim Jung-Lye , Ha Geun-Hyoung , Breuer Eun-Kyoung
Published: July 2017

Tankyrases (TNKS1 and TNKS2) are members of the human poly(ADP-ribose) polymerase (PARP) family and catalyze PARsylation by using NAD+ as a substrate to modify various proteins in order to regulate various cellular processes including Wnt/β-catenin signaling. TNKS1 has been shown to be overexpressed and to be correlated with highly aggressive disease and prognosis in various types of human cancers. A small molecule inhibitor of TNKS1, XAV-939 has been proven to be a potent inhibitor of Wnt/β-catenin signaling by stabilizing Axin. However, the effect of tankyrase inhibitors as potential breast cancer therapy is still under investigation. In this study, we found that TNKS1 is highly expressed in breast cancer cell lines, particularly in triple-negative breast cancer (TNBC) cells and that the expression of TNKS1 correlates with anti-proliferative efficacy of tankyrase inhibitors, XAV-939 and JW55. Also, XAV-939 treatment suppressed cell migration and invasion capabilities and epithelial-mesenchymal transition (EMT) signaling in triple-negative breast cancer cell lines. Moreover, XAV-939 reduced expression of stemness markers. It was shown that polo-like kinase 1 (PLK1) functions as a positive regulator of TNKS1 protein stability. Interestingly, we found that combination treatment of XAV-939 with PLK inhibitor GW843682X significantly suppressed cell growth, clonogenic potential, migratory and invasive capabilities of breast cancer cells. The combination of XAV-939 with ionizing radiation (IR) also showed an additional therapeutic effect. Therefore, our findings highlight the important value of TNKS1 as a therapeutic target and suggest the potential for improving the clinical efficacies of tankyrase inhibitors in combination with either PLK inhibitors or radiotherapy for patients with triple-negative breast cancer.

Citation Format: Maya Mathew, Loredana Campo, Jung-Lye Kim, Geun-Hyoung Ha, Eun-Kyoung Breuer. Targeting tankyrases as a therapeutic strategy for triple-negative breast cancer [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 1119. doi:10.1158/1538-7445.AM2017-1119
Abstract 112: Identifying drugs that target ovarian cancer tumor initiating cells
Authors: Ozaki Michelle K. , House Carrie D. , Annunziata Christina M.
Published: July 2017

Ovarian cancer is the most lethal gynecological cancer, with overall five-year survival for women with advanced disease being at only 25%. The current standard of care is treatment with a platinum-based chemotherapy drug. Unfortunately, a subpopulation of tumor cells often persists, contributing to platinum-based chemotherapy resistance and disease recurrence. In this study we investigated drugs to target these putative tumor-initiating cells (TICs), and explored the pathways of these drugs in both adherent proliferative cell culture conditions and non-adherent TIC-enriched cultures. We conducted a drug screen under both growth conditions, in order to identify compounds that are able to inhibit growth of TICs. Of the drugs identified, we focused further efforts on those involved with inhibiting the NF-kappaB pathway because prior studies have linked NF-kappaB activity with drug resistance and poor survival. Cell viability assays done with the four drugs, bardoxolone methyl, salinomycin, disulfiram, and elesclomol, show these drugs inhibit the growth of ovarian cancer cell lines both as TICs and in corresponding adherent cultures. Disulfiram showed preferential killing of TICs in some of the cell lines tested. All drugs showed some evidence for inhibiting NF-kappaB on Western blot, and ability to decrease CD133/ALDH double-positive TICs on flow cytometry. Carboplatin is known to kill proliferative ovarian cancer cells, and increase the relative percentage of CD133/ALDH positive TICs. Our ongoing studies will address combination of each drug with carboplatin, with the hypothesis that these drugs will increase in vivo efficacy by suppressing TICs, and thereby decrease recurrence of platinum-resistant ovarian cancer.

Citation Format: Michelle K. Ozaki, Carrie D. House, Christina M. Annunziata. Identifying drugs that target ovarian cancer tumor initiating 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 112. doi:10.1158/1538-7445.AM2017-112
Abstract 1120: Chronopharmacology of cisplatin: role of the circadian rhythm in modulating cisplatin-induced toxicity in melanoma mouse model
Authors: Dakup Panshak , Porter Kenneth , Gajula Rajendra , Gaddameedhi Shobhan
Published: July 2017

Purpose: The goal of this research is to highlight novel and divergent molecular mechanisms of the circadian system in modulating the response of cisplatin therapy against melanoma tumors. Cisplatin is one of the most commonly used chemotherapeutic drugs in treating a variety of tumors including cancers of ovaries, testis, lungs, blood and solid tumors of the head and neck, and is more recently under clinical trials for potential application in melanoma tumors. However, the major limitation of cisplatin as a chemotherapeutic drug is its tumor resistance and nephrotoxicity. Hence, improving the effectiveness and reducing the toxicities associated with cisplatin therapy are desirable outcomes. Studies on human models have shown decreased renal and blood toxicity by time-of-the-day. Consequently, our project seeks to study the chronopharmacological effects and understand the mechanisms that have been successfully demonstrated in human models. We hypothesize a mechanistic, circadian rhythm-based cause for these outcomes.

Experimental Design: Studies were done on B16F10 melanoma mouse models of wild-type and circadian disrupted Per1/2 -/- animals treated with 3 doses of 5 mg/kg cisplatin in the morning (7 AM) and evening (5 PM). Animal weights and tumor sizes were measured regularly post-treatment. Upon sacrifice, tissues (skin, kidney, and tumor) were harvested and analyzed for cisplatin-induced toxicities and DNA damage responses using H & E staining, western blot, and KIM-1 and immuno-slot blot assays.

Results: Weight measurements show a clock-regulated response to cisplatin toxicity. AM-treated wild-type animals showed significant weight loss compared to PM-treated wild-type animals. This treatment time differential is lost in the Per1/2 -/-. On a molecular level, kidney tissue DNA samples showed clock-controlled cisplatin-DNA repair activity in wild-type animals compared to Per1/2 -/-. These initial findings strongly suggest that nephrotoxicity and DNA damage response function might be regulated by the circadian rhythm.

Conclusions: These findings indicate a possible mechanism for the chronopharmacology of cisplatin in minimizing the toxicity associated with it and reveal a target for future study of additional mechanistic causes of circadian dosing changes in cisplatin and other genotoxic stress-mediated anti-cancer agents.

Citation Format: Panshak Dakup, Kenneth Porter, Rajendra Gajula, Shobhan Gaddameedhi. Chronopharmacology of cisplatin: role of the circadian rhythm in modulating cisplatin-induced toxicity in melanoma mouse model [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 1120. doi:10.1158/1538-7445.AM2017-1120
Abstract 1123: Sphingolipids transfer proteins (GLTP and CPTP) regulate the neoplastic progression of colon and breast cancer cells
Authors: Mishra Shrawan K. , Brown Rhoderick E.
Published: July 2017

Sphingolipids have previously been shown to affect cancer progression by regulating cell death (apoptosis) and survival (autophagy). While apoptosis is promoted by elevations in sphingosine and ceramide, increases in sphingosine-1-phosphate and ceramide-1-phosphate can tip the balance toward survival. Changes in the expression of sphingolipid transfer proteins such as GLTP (glycolipid transfer protein) and CPTP (ceramide-1-phosphate transfer protein) have been shown to modulate cell shape change and regulate pro-inflammatory cytokine release, respectively, in human cancer epithelial cell lines. To gain a better understanding of the situation, we investigated further. We discovered that GLTP overexpression inhibits the growth of human colon carcinoma cell lines (HT-29; HCT-116), but spares normal colonic epithelial cells (HCEC) largely due to growth arrest at the G0/G1 cell cycle checkpoint. Mechanistically, we found that GLTP overexpression modulated cell cycle progression by upregulating Kip1/p27 and Cip1/p21 protein and mRNA levels, while decreasing CDK2, CDK4, cyclin E and cyclin D1 protein levels. The cell cycle arrest and growth inhibition induced by GLTP overexpression led to apoptotic cell death of HT-29 cells. Neither GLTP nor CPTP overexpression induced apoptosis in breast cancer cell lines (T47D and HTB-126). However, depletion of CPTP, but not GLTP, induced autophagy as indicated by increased LC3 transcript and autophagosome levels (GFP-LC3-II puncta). In the breast cancer cell lines, increased transcript levels of cPLA2 and CERK were detected consistent with the earlier pro-inflammatory effect reported for CPTP depletion in A549 lung epithelial carcinoma cells. Our findings shed light on the mechanistic ways by which GLTP and CPTP affect apoptosis and autophagy to impact cancer progression. Future in vivo studies are planned to ascertain the role(s) of these new players in cancer development and therapy.

[Support: NIH GM45928, HL-125353, Paint-the-Town-Pink (PTTP) Cancer Funds, Hormel Fdn]

Citation Format: Shrawan K. Mishra, Rhoderick E. Brown. Sphingolipids transfer proteins (GLTP and CPTP) regulate the neoplastic progression of colon and breast cancer 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 1123. doi:10.1158/1538-7445.AM2017-1123
Abstract 1124: Assessment of HRD score as predictor of chemosensitivity of PDAC PDX xenograft models to DNA-damaging chemotherapy
Authors: Khazak Vladimir , Skobeleva Natalia , Vetkina Anastasiia , Serebriiskii Ilya , Timms Kirsten M. , Davies Angela , Astsaturov Igor
Published: July 2017

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy that affects 44,000 individuals annually in the US, with almost 90% lethality even when diagnosed prior to metastasis. There is an urgent unmet medical need both for new therapies as well as better matching of existing therapies to patients. To address this emergency, we are assessing the feasibility of implementing a strategy of using HRD (Homologous Recombination Deficiency) scores for better therapy matching in PDAC patients. Using a panel of 77 patient-derived xenograft (PDX) models that were developed from fresh surgical PDAC tumor samples, HRD scores were generated based on analysis of three biomarkers (LOH, TAI and LST) and mutational data for 45 genes. All 77 samples met inclusion criteria, 75 FFPE specimens generated mutation data. HRD analysis was successful for 71 specimens (range= 1 - 63 (median=22)), with the primary cause of failure identified as high non-tumor content. 53 PDX models had mutations in KRAS gene and 45 in TP53. We have also identified 4 PDX models with mutations in BRCA2, 3 models with mutations in ATM, 4 models with mutations in RAD51. We have also found frequent mutations in several other DNA repair genes (ATR, PALB2, MLH1, MSH2, MSH3, MSH6, FANCM), but most of these models retained one functional allele and were not associated with a high HRD score. Using this genomic analysis, all 71 PDX models were stratified into three clusters with high, medium and low HRD scores. Three PDX models with the highest and lowest HRD scores each were selected for an in vivo study with DNA-damaging platinum-based chemotherapeutic agents Cisplatin and Carboplatin, as well as with a clinically relevant PARP inhibitor Niraparib. The results of the PDX study will be reported and compared with responses to chemotherapy using RECIST V1.1 in patients.

Note: This abstract was not presented at the meeting.

Citation Format: Vladimir Khazak, Natalia Skobeleva, Anastasiia Vetkina, Ilya Serebriiskii, Kirsten M. Timms, Angela Davies, Igor Astsaturov. Assessment of HRD score as predictor of chemosensitivity of PDAC PDX xenograft models to DNA-damaging chemotherapy [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 1124. doi:10.1158/1538-7445.AM2017-1124
Abstract 1127: Aberrant nuclear expression of GSK-3beta in human head and neck carcinoma
Authors: Matsangou Maria , Ugolkov Andrey , Taxter Timothy J. , Samant Sandeep , Mazar Andrew P. , Giles Francis J.
Published: July 2017

Background: Recurrent/metastatic head and neck squamous cell carcinoma (SCCHN) and salivary gland malignancies are difficult to treat with limited standard of care options at the present time. Glycogen Synthase Kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been implicated as a potential therapeutic target in human cancer. Our in vivo studies demonstrated that our novel GSK-3 inhibitors significantly potentiated the effects of conventional chemotherapy in patient-derived xenograft models of glioblastoma and breast cancer leading to regression of tumors. In order to develop a rationale to test our novel GSK-3 inhibitors in head and neck (H&N) malignancies, we evaluated the expression pattern of GSK-3beta in human H&N benign tissue and malignant tumors.

Methods: We used immunohistochemical staining of H&N tumor tissue Microarray (TMA), 48 total cases (20 benign tissues, 28 malignant), to study the expression pattern of GSK-3beta. GSK-3beta nuclear accumulation was defined as positive staining of more than 50% of cancer cell nuclei throughout the tumor regardless of cytoplasmic staining.

Results: Of the 20 malignant H&N samples (15 SCCHN, 1 nasopharyngeal and 5 other histology), 13 (65%) were found to have aberrant nuclear accumulation of GSK-3beta. Amongst SCCHN, 73% (11 of 15 samples) had aberrant nuclear accumulation of GSK-3beta. In contrast, none (0%) of the 11 benign non-salivary H&N tissue showed detectable expression of GSK-3beta. Of interest, 60% of salivary adenoid cystic carcinoma specimens and 44% of benign salivary gland tissue showed GSK-3beta expression.

Conclusions: Our results demonstrate for the first time, that there is aberrant nuclear expression of GSK-3beta in SCCHN. This finding supports further exploring of our novel GSK-3beta inhibitor as a potential therapeutic target for recurrent/metastatic SCCHN and also, as a potential prognostic and predictive biomarker for risk of recurrent disease and chemo- or radio-resistance. Its role in salivary gland malignancies requires further studying.

Citation Format: Maria Matsangou, Andrey Ugolkov, Timothy J. Taxter, Sandeep Samant, Andrew P. Mazar, Francis J. Giles. Aberrant nuclear expression of GSK-3beta in human head and neck carcinoma [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 1127. doi:10.1158/1538-7445.AM2017-1127
Abstract 113: Evaluating the anticancer activity of two flexible heteroarotinoid analogs on breast cancer
Authors: Ginn Emily , Zou Hongye , Fallatah Maryam M. , Liu Shengquan , Louie Maggie C.
Published: July 2017

Flexible heteroarotiniods (flex-hets) are compounds derived from retinoic acid and recent studies have indicated that these compounds exhibit anti-cancer activity. Amongst the flexible heteroarotinoids, SHetA2 has been to shown block the growth of cervical, head and neck, kidney, lung, and ovarian cancers, and most recently, prostate and breast cancers. However, due to SHetA2’s limitations— a high degree of hydrophobicity, non-selectivity, and potential liver toxicity— a second generation of analogs was developed. Results from our recent study suggest that one of the second-generation analogs, 1-(1-(naphthalen-1-yl)ethyl)-3-(4-nitrophenyl)thiourea (SL-1-09) exhibits anti-cancer activities against both ERα+ and ER- breast cancer cells at micromolar concentrations. Since SL-1-09 is a racemic mixture, the R (SL-1-29) and S (SL-1-30) enantiomers were purified and investigated for their anti-cancer properties. Our results suggest that SL-1-30 has greater growth inhibitory effects on T47D, MCF7, MDA-MB-453, MDA-MB-468 cells in comparison to SL1-29, suggesting that the activity observed in SL-1-09 is likely associated with the S enantiomer. Consistent with this data, breast cancer cells treated with SL-1-09 and SL-1-30 express lower levels of proteins that regulate the cell cycle (i.e, cyclin A, cyclin B, cyclin D1, cyclin E and cdk2). These results demonstrate that SL-1-30 and SL-1-09 inhibit breast cancer cell growth, potentially by blocking cell cycle progression, however further studies are necessary for determining the mechanisms of action.

Citation Format: Emily Ginn, Hongye Zou, Maryam M. Fallatah, Shengquan Liu, Maggie C. Louie. Evaluating the anticancer activity of two flexible heteroarotinoid analogs on breast cancer [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 113. doi:10.1158/1538-7445.AM2017-113
Abstract 1133: Discovery of novel small molecule inhibitors of RNA-binding protein Musashi-1
Authors: Lan Lan , Smith Amber , Wu Xiaoqing , Roy Anuradha , Gowthaman Ragul , Karanicolas John , Somoza Amber D. , Wang Clay C.C. , Oakley Berl , Guzman Roberto De , Neufeld Kristi , Xu Liang
Published: July 2017

1) Background and Objective: Musashi-1(Msi1) is an RNA-binding protein that negatively regulates translation by binding to the 3′-UTRs of target mRNAs including Numb, APC and p21WAF-1, key regulators of Notch, Wnt signaling and cell cycle progression, respectively. We aim to identify small molecule inhibitors of Msi1’s mRNA-binding activity thus blocking the growth of a broad range of cancer cells.

2) Methods: Fluorescence polarization assay was used to screen for small molecules that disrupt the binding of Msi1 to its consensus RNA binding site. Hits were validated by surface plasmon resonance, amplified luminescent proximity homogeneous assay and nuclear magnetic resonance.

3) Results: Among ~2,000 small molecules we screened, we found several clusters of compounds that disrupt the Msi1-numb RNA binding potently, including natural products, herbal extracts and fungal metabolites. One of the clusters is the derivatives of the secondary metabolites from Aspergillus nidulans. The top hit, Aza-9, from this cluster was validated by amplified luminescent proximity homogeneous assay. Further validation by surface plasmon resonance and nuclear magnetic resonance indicate that Aza-9 binds to Msi1 directly, in the RNA binding pocket.

4) Discussion and Conclusions: Our study supports the hypothesis that Msi1 inhibition is a viable and effective anti-cancer strategy. More target validation assays will be carried out for the compounds from other clusters.

Citation Format: Lan Lan, Amber Smith, Xiaoqing Wu, Anuradha Roy, Ragul Gowthaman, John Karanicolas, Amber D. Somoza, Clay C.C. Wang, Berl Oakley, Roberto De Guzman, Kristi Neufeld, Liang Xu. Discovery of novel small molecule inhibitors of RNA-binding protein Musashi-1 [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 1133. doi:10.1158/1538-7445.AM2017-1133
Abstract 1141: Evaluation of GABRP as a novel therapeutic target in triple negative breast cancer
Authors: Wali Vikram B. , Patwardhan Gauri A. , Hatzis Christos , Pusztai Lajos
Published: July 2017

Triple Negative breast cancers (TNBC) represent nearly 20% of all breast cancers but do not have any targeted therapies available due to lack of amplification of HER2 and expression of estrogen and progesterone receptors. To identify potentially druggable targets for TNBC, we compared TNBC to non-TNBC tumors in large independent gene expression clinical datasets to identify highly expressed genes in TNBC that encode for proteins expressed on the cell surface. We found gamma-aminobutyric acid type A receptor pi (GABRP) to be the most overexpressed receptor protein gene in TNBC, while its expression in normal tissues was low and comparable to that of proteins targeted by drugs or therapeutic antibodies already in clinical testing. We compared GABRP mRNA and protein expression across panel of breast cancer cell lines and found it to be particularly elevated in HCC1143 and MDA-MB-468 TNBC cells. Knockdown of GABRP using siRNA suppressed TNBC cell growth and stable GABRP knock-down by shRNA suppressed growth of MDA-MB-468 xenografts in nude mice. Sub-cellular fractionation of TNBC cells and subsequent Western blot analysis confirmed that GABRP is located predominantly in the cell membrane. GABRP protein expression on cell surface was also detected by flowcytometry. Interestingly, treatment with 5-100μg/ml of anti-GABRP antibody that binds to the extracellular domain (ECD) itself inhibited growth of TNBC cell lines expressing higher GABRP, while the same doses of a control antibody had no effect in these cells in culture. Our goal is to generate an antibody drug conjugate (ADC) for TNBC by conjugating anti-GABRP antibody with a maytansinoid such as DM1, which has proven cytotoxicity in breast cancer cells. Together, our results suggest that GABRP is a potential therapeutic target for triple-negative breast cancers.

Citation Format: Vikram B. Wali, Gauri A. Patwardhan, Christos Hatzis, Lajos Pusztai. Evaluation of GABRP as a novel therapeutic target in triple negative breast cancer [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 1141. doi:10.1158/1538-7445.AM2017-1141