Maureen Highkin - Academia.edu (original) (raw)

Papers by Maureen Highkin

Phosphoproteins in Volcano Plot

Supplementary Figure 1. Ulixertinib potentiates gemcitabine effect and this combination is well t... more Supplementary Figure 1. Ulixertinib potentiates gemcitabine effect and this combination is well tolerated in mice; Supplementary Figure 2. Pharmacologic ERK inhibition increases p-MEK, ERK and AKT; Supplementary Figure 3. Ulixertinib synergizes with HER inhibitors; Supplementary Figure 4. Ulixertinib synergizes with PI3K Inhibitor

Bio/Technology, 1993

We have engineered mammalian cell lines to produce high levels of heterologous proteins by constr... more We have engineered mammalian cell lines to produce high levels of heterologous proteins by constructing a cell line that expresses the herpesvirus transactivator, VP16. Subsequent stable transfection with a gene of interest under control of a herpesvirus immediate early promoter led to a rapid isolation of cell lines producing between 1 and 20 micrograms of protein/million cells/24 hours. This high level expression is stable for at least five months.

Cancer Research

Background: HER2 activating mutations occur in 2-5% of metastatic breast cancer (MBC) patients, a... more Background: HER2 activating mutations occur in 2-5% of metastatic breast cancer (MBC) patients, and three phase II or basket clinical trials have shown that the irreversible pan-HER tyrosine kinase inhibitor, neratinib, has good single agent efficacy for HER2 mutated MBC patients. Current trials are combining neratinib with other targeted therapies to increase response rate and progression free survival for these patients. Methods: We established patient derived xenografts (PDX) and organoids from two patients with HER2 mutated, non-amplified MBC and used them to test neratinib with the antibody drug conjugates (ADC’s), trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), both in 3D culture and in vivo. Real time, in vivo uptake of these ADC’s was visualized with a near infrared fluorophore. Results: PDX lines WHIM51 and WHIM64 were established from ER+, HER2 non-amplified MBC patients that had HER2 activating mutations. WHIM51 has HER2 exon 20 insertion mutation at ami...

Neurology 35(4 Suppl, Dec 20, 1985

Journal of Virology, 1984

Mouse hepatitis virus strain A59 produces chronic central nervous system demyelination in rodents... more Mouse hepatitis virus strain A59 produces chronic central nervous system demyelination in rodents. As late as 6 months after intracerebral inoculation of mice 4 to 6 weeks old, when infectious virus cannot be recovered and viral antigens cannot be detected in the central nervous systems and livers of these animals, primary demyelination is still evident. Using cloned virus-specific DNAs and the highly sensitive and specific technique of in situ hybridization, we have detected low levels of mouse hepatitis virus A59 RNA in the central nervous systems and livers of mice 10 months after inoculation. We suggest that viral persistence may play a role in mouse hepatitis virus A59-induced chronic demyelination.

$Research paper thumbnail of Phase II trial of levocetirizine with capecitabine and bevacizumab to overcome the resistance of antiangiogenic therapies in refractory metastatic colorectal cancer$

Journal of Clinical Oncology, 2015

763 Background: Despite clinical success of VEGF blockade in mCRC, resistance to anti-angiogenic ... more 763 Background: Despite clinical success of VEGF blockade in mCRC, resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in resistance development to anti-angiogenic therapy. Levocetirizine is a third generation antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC. Methods: This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850mg/m2 – 7 days on and 7 days off, IV bevacizumab 5 mg/kg every 14 days and oral levocetirizine 5 mg daily in 14 day cycles. The primary end point was PFS and secondary endpoints included ORR and tolerability. An exploratory endpoint included correlation of PFS with cytokine (IL-8 & IL-6) levels. A sample size of 36 evaluable patients could identi...

Laboratory investigation; a journal of technical methods and pathology, 1988

The spread of a neurotropic coronavirus, mouse hepatitis virus strain A59, in the mouse central n... more The spread of a neurotropic coronavirus, mouse hepatitis virus strain A59, in the mouse central nervous system was studied after intranasal inoculation. Mouse hepatitis virus strain A59 spread during the 3- to 5-day postinoculation period, through the olfactory pathway into the limbic system. Coronavirus particles were detected in the limbic system by electron microscopy. The combination of temporal propagation through an anatomical-physiological central nervous system pathway and anatomical restriction of viral infection suggests that specific interneuronal transport is important in spread of the virus. This experimental system may represent a model for diseases associated with human coronaviruses (common cold viruses) and/or the human limbic system.

SLAS Discovery, 2011

To facilitate discovery of compounds modulating sphingosine-1-phosphate (S1P) signaling, the auth... more To facilitate discovery of compounds modulating sphingosine-1-phosphate (S1P) signaling, the authors used high-throughput mass spectrometry technology to measure S1P formation in human whole blood. Since blood contains endogenous sphingosine (SPH) and S1P, mass spectrometry was chosen to detect the conversion of an exogenously added 17-carbon-long variant of sphingosine, C17SPH, into C17S1P. The authors developed procedures to achieve homogeneous mixing of whole blood in 384-well plates and for a method requiring minimal manipulations to extract S1P from blood in 96- and 384-well plates prior to analyses using the RapidFire® mass spectrometry system.

In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in theP... more In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in thePIK3CA,TP53, or E-cadherin genes. Of these co-occurring mutations,HER2andPIK3CAmutations are the most prevalent gene pair, with approximately 40% ofHER2mutated breast cancers also having activating mutations inPIK3CA. To study the effects of co-occurringHER2andPIK3CAmutations, we bred genetically engineered mice with theHER2V777L;PIK3CAH1047Rtransgenes (HP mice) and studied the resulting breast cancers bothin vivoas well asex vivousing cancer organoids. HP breast cancers show accelerated tumor formationin vivoand increased invasion and migration inin vitroassays. HP breast cancers have resistance to the pan-HER tyrosine kinase inhibitor, neratinib, but are effectively treated by neratinib plus trastuzumab deruxtecan. Proteomic and RNA-Seq analysis of HP breast cancers showed increased gene expression of Cyclin D1 and p21WAF1/Cip1 and changes in cell cycle markers. Combining neratinib with...

Nature Communications

Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approxim... more Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis (RAMS). We prioritize RAMS11 due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevated RAMS11 expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrate RAMS11-dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α). Overall, recent clinical trials using topoisomerase inhibitors coupled with our finding...

Molecular and Cellular Biology / Genetics

Molecular cancer therapeutics, Jan 31, 2018

Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need.... more Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting KRAS, the oncogene that is present in >95% of PDAC, is a heavily pursued strategy, but remains unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncoprotein, particularly the mitogenic RAF-MEK-ERK pathway represents the next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to re-activate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. Ulixertinib (or BVD-523) is a first-in-class ERK-specific inhibitor that has demonstrated promising anti-tumor activity in a phase 1 clinical trial for advanced solid tumors with NRAS and BRAF mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ul...

Journal of medicinal chemistry, Jan 23, 2017

Sphingosine kinase (SphK) is the major source of the lipid mediator and GPCR agonist sphingosine-... more Sphingosine kinase (SphK) is the major source of the lipid mediator and GPCR agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound 22a (PF-543) with two orders of magnitude improved potency. Compound 22a inhibited SphK1 with an IC50 of 2 nM and was more than 100-fold selective for SphK1 over the SphK2 isoform. Through the modification of tail region substituents, the specificity of inhibition for SphK1 and SphK2 could be modulated yielding SphK1 selective, potent SphK1/2 dual, or SphK2 preferential inhibitors.

Advances in Experimental Medicine and Biology, Feb 1, 1984

Journal of Biomolecular Screening, 2011

To facilitate discovery of compounds modulating sphingosine-1-phosphate (s1p) signaling, the auth... more To facilitate discovery of compounds modulating sphingosine-1-phosphate (s1p) signaling, the authors used high-throughput mass spectrometry technology to measure s1p formation in human whole blood. since blood contains endogenous sphingosine (sph) and s1p, mass spectrometry was chosen to detect the conversion of an exogenously added 17-carbon-long variant of sphingosine, C17sph, into C17s1p. The authors developed procedures to achieve homogeneous mixing of whole blood in 384-well plates and for a method requiring minimal manipulations to extract s1p from blood in 96-and 384-well plates prior to analyses using the RapidFire ® mass spectrometry system. (Journal of Biomolecular Screening 2011;16:272-277)