Evan Dick - Academia.edu (original) (raw)

Papers by Evan Dick

Cancer Research

Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for m... more Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for many late-stage solid tumors are lacking. Ovarian cancer alone kills 14,000 people each year, and many patients do not respond to currently available treatments. Here we introduce CTIM-76, a CLDN6 T-cell engager antibody as a potential treatment of ovarian, endometrial, and other solid tumors. The tight junction protein Claudin 6 (CLDN6) is a validated therapeutic target for many solid tumor types, including ovarian, endometrial, testicular, and gastric. It is differentially expressed on cancer cells with no reported expression in normal, healthy tissue. Despite being an attractive target, therapeutic monoclonal antibodies (MAbs) targeting CLDN6 are difficult to discover due to an abundance of closely related family members and an absolute need for high specificity. The extracellular region of CLDN6 closely resembles the widely expressed family member CLDN9 (3 amino acids different). The ...

Journal of the American Geriatrics Society, 1996

Springer eBooks, 1982

The vertebrate retina contains a variety of neuronal con-nections which depend on chemical commun... more The vertebrate retina contains a variety of neuronal con-nections which depend on chemical communication. Both excitatory and inhibitory synapses are present: A substantial list of putative transmitter agents has been expanded in recent years by techniques which have localized several peptides to the retina (Brecha and Karten, 1979; Stell et al., 1980). The physiologist who attempts to define transmitter action in the retina does not suffer from an abbreviated list of agents which may subserve secretory transmission. We have studied the action of several transmitter candidates and their antagonists using intracellular recording techniques in the perfused retina-eyecup preparation of the mudpuppy (Necturus maculosus). We have also studied the effects of several peptides which have been localized to the mudpuppy retina through immunohistochemical techniques of Brecha and Karten. Our findings support the concept that excitatory and inhibitory amino acids, as well as some peptides may be involved in synaptic transmission.

Investigative Ophthalmology & Visual Science, 1980

Drug Safety

Introduction Antiprogestins have demonstrated promising activity against breast and gynecological... more Introduction Antiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure. Objective We explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I-II studies involving patients with breast, ovarian, endometrial, and prostate cancer. Results Among the 88 patients in two phase I-II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient's liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist. Conclusions These results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.

Thesis (Ph. D.)--State University of New York at Buffalo, 1979. Typescript.

Neuroscience Letters, 1981

Neurotensin, substance P and (D-Ala2, Met5)-enkephalinamide were iontophoresed onto ganglion cell... more Neurotensin, substance P and (D-Ala2, Met5)-enkephalinamide were iontophoresed onto ganglion cells of the amphibian retina. Substance P and neurotensin were found to be excitatory while (D-Ala2, Met5)-enkephalinamide suppressed all types of ganglion cells. These findings are consistent with a functional role for peptides in the vertebrate retina.

Journal of Pharmaceutical Marketing & Management, 1996

Journal of Neurochemistry, 1984

The distributions of glycine, y-aminobutyric acid (GABA), glutamate decarboxylase (EC 4.1.1.15), ... more The distributions of glycine, y-aminobutyric acid (GABA), glutamate decarboxylase (EC 4.1.1.15), and GABA transaminase (EC 2.6.1.19) were determined in rabbit and mudpuppy retinas. In both species, peak levels of the amino acids and the enzymes occurred in the inner plexiform layer. Glutamate decarboxylase was almost entirely confined to the inner plexiform layer. Determinations were also made of the GABA content of 107 individual putative amacrine cell somas from mudpuppy retina. About 30% of those somas were found to have high endogenous GABA levels. Key Words: Glycine in retina-GABA in retina-Glutamate decarboxylase in retina-GABA transaminase in retina. Dick E. and Lowry 0. H. Distribution of glycine, y-aminobutyric acid, glutamate decarbox ylase, and y-aminobutyric acid transaminase in rabbit and mudpuppy retinas. J .

The Journal of General Physiology, 1985

Electroretinogram (ERG) and extracellular potassium activity (K+o) measurements were carried out ... more Electroretinogram (ERG) and extracellular potassium activity (K+o) measurements were carried out in isolated superfused rabbit eyecup preparations under control conditions and during the application of pharmacological agents that selectively modify the light-responsive retinal network. Light-evoked K+o changes in the rabbit (E-type) retina resemble those previously described in amphibian (I-type) retinas. Different components of the light-evoked K+o changes can be distinguished on the bases of retinal depth, V vs. log I properties, and their responses to pharmacological agents. We find two separable sources of light-evoked increases in extracellular K+: a proximal source and a distal source. The properties of the distal light-evoked K+o increase are consistent with the hypothesis that it initiates a K+-mediated current through Müller cells that is detected as the primary voltage of the electroretinographic b-wave. These experiments also support previous studies indicating that both ...

Brain Research, 1978

Miiller cells, the principal glial element of the vertebrate retina, appear to generate several c... more Miiller cells, the principal glial element of the vertebrate retina, appear to generate several components of the electroretinogram (ERG). Evidence in favor of this view has been obtained from both intra-and extraceUular electrophysiological studies 4,9,10,23. It has been assumed that light-evoked Miiller cell responses are mediated by alterations in extracellular potassium activity (K+0) 7,19. Manipulations of external K ÷ in the frog retina seemed to favor this interpretation 11. Thus, a light-evoked increase in K+0 in the distal retina was considered to be the mechanism of Mtiller cell depolarization which gives rise to the b-wave. An increased K+0 at light-offwas suggested as the mechanism for d-wave generation in amphibian retina 9. An additional ERG component termed slow Pill is thought to originate from Miiller ceils as a light-evoked hyperpolarization initiated by a K+0 decrease similar to the mechanism proposed for c-wave generation (refs. 4, 18 and 231). Recently, several laboratories have measured intraretinal K+o using ion-selective microelectrodes. These laboratories appear to be in agreement, in that a light-evoked increase in K+0 is detected in the proximal retina, but no appropriate change in K+0 was detected in the distal retina at the site of b-wave generation 6,15-17,~°. In the distal retina a light-evoked decrease in K+0 was detected, and this mechanism appears to account for the generation of the c-wave of the ERG, and perhaps slow Pill as welP 6.17.2~-24. This latter component displays a source and sink distribution consistent witha Miiller cell

Journal of …, 1985

The activity of glucose-I ,6-bisphosphatase and the level of its substrate were measured in 16 gr... more The activity of glucose-I ,6-bisphosphatase and the level of its substrate were measured in 16 gray areas and four fiber areas of mouse brain and 10 layers or sublayers of monkey retina. Because of the low activity of the enzyme and the small sample sizes, it was necessary to develop a method with two different amplification steps (overall amplification about 10'). T h e enzyme ranged in activity 100-fold from a low in monkey retina photoreceptor cells t o a high in the pyramidal layer of the hippocampus. However, in gray areas of the brain proper the range was only about fourfold. This, together with its requirement for IMP, suggests that the enzyme has a widespread metabolic function related t o states of increased neuronal activity. Glucose-I ,6-bisphosphate levels varied from 80 to 960 pmolikg dry weight in different areas of mouse brain and from 44 to 200 pmolikg dry weight in different layers of monkey retina. In general, the glucose bisphosphate levels correlated positively with the bisphosphatase activities; however, the three areas with the highest enzyme concentrations did not fit this pattern. Key Words: Brain glucose bisphosphatase-Brain glucose-1,6-bisphosphate-Retina glucose bisphosphatase. Yip V. et al. Distribution of glucose-I ,6bisphosphate and IMP-activated glucose bisphosphatase in brain and retina.

Journal of Neurochemistry, 1984

Cancer Research

Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for m... more Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for many late-stage solid tumors are lacking. Ovarian cancer alone kills 14,000 people each year, and many patients do not respond to currently available treatments. Here we introduce CTIM-76, a CLDN6 T-cell engager antibody as a potential treatment of ovarian, endometrial, and other solid tumors. The tight junction protein Claudin 6 (CLDN6) is a validated therapeutic target for many solid tumor types, including ovarian, endometrial, testicular, and gastric. It is differentially expressed on cancer cells with no reported expression in normal, healthy tissue. Despite being an attractive target, therapeutic monoclonal antibodies (MAbs) targeting CLDN6 are difficult to discover due to an abundance of closely related family members and an absolute need for high specificity. The extracellular region of CLDN6 closely resembles the widely expressed family member CLDN9 (3 amino acids different). The ...

Journal of the American Geriatrics Society, 1996

Springer eBooks, 1982

The vertebrate retina contains a variety of neuronal con-nections which depend on chemical commun... more The vertebrate retina contains a variety of neuronal con-nections which depend on chemical communication. Both excitatory and inhibitory synapses are present: A substantial list of putative transmitter agents has been expanded in recent years by techniques which have localized several peptides to the retina (Brecha and Karten, 1979; Stell et al., 1980). The physiologist who attempts to define transmitter action in the retina does not suffer from an abbreviated list of agents which may subserve secretory transmission. We have studied the action of several transmitter candidates and their antagonists using intracellular recording techniques in the perfused retina-eyecup preparation of the mudpuppy (Necturus maculosus). We have also studied the effects of several peptides which have been localized to the mudpuppy retina through immunohistochemical techniques of Brecha and Karten. Our findings support the concept that excitatory and inhibitory amino acids, as well as some peptides may be involved in synaptic transmission.

Investigative Ophthalmology & Visual Science, 1980

Drug Safety

Introduction Antiprogestins have demonstrated promising activity against breast and gynecological... more Introduction Antiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure. Objective We explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I-II studies involving patients with breast, ovarian, endometrial, and prostate cancer. Results Among the 88 patients in two phase I-II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient's liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist. Conclusions These results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.

Thesis (Ph. D.)--State University of New York at Buffalo, 1979. Typescript.

Neuroscience Letters, 1981

Neurotensin, substance P and (D-Ala2, Met5)-enkephalinamide were iontophoresed onto ganglion cell... more Neurotensin, substance P and (D-Ala2, Met5)-enkephalinamide were iontophoresed onto ganglion cells of the amphibian retina. Substance P and neurotensin were found to be excitatory while (D-Ala2, Met5)-enkephalinamide suppressed all types of ganglion cells. These findings are consistent with a functional role for peptides in the vertebrate retina.

Journal of Pharmaceutical Marketing & Management, 1996

Journal of Neurochemistry, 1984

The distributions of glycine, y-aminobutyric acid (GABA), glutamate decarboxylase (EC 4.1.1.15), ... more The distributions of glycine, y-aminobutyric acid (GABA), glutamate decarboxylase (EC 4.1.1.15), and GABA transaminase (EC 2.6.1.19) were determined in rabbit and mudpuppy retinas. In both species, peak levels of the amino acids and the enzymes occurred in the inner plexiform layer. Glutamate decarboxylase was almost entirely confined to the inner plexiform layer. Determinations were also made of the GABA content of 107 individual putative amacrine cell somas from mudpuppy retina. About 30% of those somas were found to have high endogenous GABA levels. Key Words: Glycine in retina-GABA in retina-Glutamate decarboxylase in retina-GABA transaminase in retina. Dick E. and Lowry 0. H. Distribution of glycine, y-aminobutyric acid, glutamate decarbox ylase, and y-aminobutyric acid transaminase in rabbit and mudpuppy retinas. J .

The Journal of General Physiology, 1985

Electroretinogram (ERG) and extracellular potassium activity (K+o) measurements were carried out ... more Electroretinogram (ERG) and extracellular potassium activity (K+o) measurements were carried out in isolated superfused rabbit eyecup preparations under control conditions and during the application of pharmacological agents that selectively modify the light-responsive retinal network. Light-evoked K+o changes in the rabbit (E-type) retina resemble those previously described in amphibian (I-type) retinas. Different components of the light-evoked K+o changes can be distinguished on the bases of retinal depth, V vs. log I properties, and their responses to pharmacological agents. We find two separable sources of light-evoked increases in extracellular K+: a proximal source and a distal source. The properties of the distal light-evoked K+o increase are consistent with the hypothesis that it initiates a K+-mediated current through Müller cells that is detected as the primary voltage of the electroretinographic b-wave. These experiments also support previous studies indicating that both ...

Brain Research, 1978

Miiller cells, the principal glial element of the vertebrate retina, appear to generate several c... more Miiller cells, the principal glial element of the vertebrate retina, appear to generate several components of the electroretinogram (ERG). Evidence in favor of this view has been obtained from both intra-and extraceUular electrophysiological studies 4,9,10,23. It has been assumed that light-evoked Miiller cell responses are mediated by alterations in extracellular potassium activity (K+0) 7,19. Manipulations of external K ÷ in the frog retina seemed to favor this interpretation 11. Thus, a light-evoked increase in K+0 in the distal retina was considered to be the mechanism of Mtiller cell depolarization which gives rise to the b-wave. An increased K+0 at light-offwas suggested as the mechanism for d-wave generation in amphibian retina 9. An additional ERG component termed slow Pill is thought to originate from Miiller ceils as a light-evoked hyperpolarization initiated by a K+0 decrease similar to the mechanism proposed for c-wave generation (refs. 4, 18 and 231). Recently, several laboratories have measured intraretinal K+o using ion-selective microelectrodes. These laboratories appear to be in agreement, in that a light-evoked increase in K+0 is detected in the proximal retina, but no appropriate change in K+0 was detected in the distal retina at the site of b-wave generation 6,15-17,~°. In the distal retina a light-evoked decrease in K+0 was detected, and this mechanism appears to account for the generation of the c-wave of the ERG, and perhaps slow Pill as welP 6.17.2~-24. This latter component displays a source and sink distribution consistent witha Miiller cell

Journal of …, 1985

The activity of glucose-I ,6-bisphosphatase and the level of its substrate were measured in 16 gr... more The activity of glucose-I ,6-bisphosphatase and the level of its substrate were measured in 16 gray areas and four fiber areas of mouse brain and 10 layers or sublayers of monkey retina. Because of the low activity of the enzyme and the small sample sizes, it was necessary to develop a method with two different amplification steps (overall amplification about 10'). T h e enzyme ranged in activity 100-fold from a low in monkey retina photoreceptor cells t o a high in the pyramidal layer of the hippocampus. However, in gray areas of the brain proper the range was only about fourfold. This, together with its requirement for IMP, suggests that the enzyme has a widespread metabolic function related t o states of increased neuronal activity. Glucose-I ,6-bisphosphate levels varied from 80 to 960 pmolikg dry weight in different areas of mouse brain and from 44 to 200 pmolikg dry weight in different layers of monkey retina. In general, the glucose bisphosphate levels correlated positively with the bisphosphatase activities; however, the three areas with the highest enzyme concentrations did not fit this pattern. Key Words: Brain glucose bisphosphatase-Brain glucose-1,6-bisphosphate-Retina glucose bisphosphatase. Yip V. et al. Distribution of glucose-I ,6bisphosphate and IMP-activated glucose bisphosphatase in brain and retina.

Journal of Neurochemistry, 1984