With a background as a Medical Physicist, my PhD-project (conducted in the Forssell-Aronsson Lab at University of Gothenburg) focused on peptide receptor radionuclide therapy of small intestine neuroendocrine tumors and biological effects of radiation. This research prompted a further interest in biology, and lead me to enter a postdoctoral research position in the Sarosiek Lab at Harvard University, with a focus on the regulation of apoptotic priming in response to stress such as irradiation.
Apoptosis is an evolutionarily-conserved form of cell death that is critical for normal development, tissue homeostasis, and cancer prevention. Abnormal rates of apoptosis are associated with many major diseases that impact human health worldwide, including neurodegeneration, heart failure and cancer. Despite this, little is known about the mechanisms that regulate cell death in healthy cells and their roles in maintaining human health. In brief, cellular damage releases pro-death proteins (“activators” of apoptosis), which can either be blocked by anti-apoptotic proteins, or induce apoptosis. The abundance of pro- and anti-apoptotic proteins varies between tissues, leading to differences in sensitivity to apoptotic signals. This sensitivity can be measured by BH3 profiling, which detects the extent of apoptosis induction in response to “activator” peptides. The aims of my current project are to measure apoptotic priming at a single-cell level in mammalian tissues during development, aging, and disease progression, and subsequently identify the cellular mechanisms responsible for regulation of apoptosis.
Supervisors: Eva Forssell-Aronsson, Khalil Helou, Håkan Ahlman, and Kristopher Sarosiek
Apoptosis is an evolutionarily-conserved form of cell death that is critical for normal development, tissue homeostasis, and cancer prevention. Abnormal rates of apoptosis are associated with many major diseases that impact human health worldwide, including neurodegeneration, heart failure and cancer. Despite this, little is known about the mechanisms that regulate cell death in healthy cells and their roles in maintaining human health. In brief, cellular damage releases pro-death proteins (“activators” of apoptosis), which can either be blocked by anti-apoptotic proteins, or induce apoptosis. The abundance of pro- and anti-apoptotic proteins varies between tissues, leading to differences in sensitivity to apoptotic signals. This sensitivity can be measured by BH3 profiling, which detects the extent of apoptosis induction in response to “activator” peptides. The aims of my current project are to measure apoptotic priming at a single-cell level in mammalian tissues during development, aging, and disease progression, and subsequently identify the cellular mechanisms responsible for regulation of apoptosis.
Supervisors: Eva Forssell-Aronsson, Khalil Helou, Håkan Ahlman, and Kristopher Sarosiek
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Papers by J. Spetz
211At-labeled radiopharmaceuticals are potentially useful for tumor therapy. However, a limitation
has been the preferential accumulation of released 211At in the thyroid gland, which
is a critical organ for such therapy. The aim of this study was to determine the effect of
absorbed dose, dose-rate, and time after 211At exposure on genome-wide transcriptional
expression in mouse thyroid gland.
Methods
BALB/c mice were i.v. injected with 1.7, 7.5 or 100 kBq 211At. Animals injected with 1.7 kBq
were killed after 1, 6, or 168 h with mean thyroid absorbed doses of 0.023, 0.32, and 1.8 Gy,
respectively. Animals injected with 7.5 and 100 kBq were killed after 6 and 1 h, respectively;
mean thyroid absorbed dose was 1.4 Gy. Total RNA was extracted from pooled thyroids
and the Illumina RNA microarray platform was used to determine mRNA levels. Differentially
expressed transcripts and enriched GO terms were determined with adjusted p-value
<0.01 and fold change >1.5, and p-value <0.05, respectively.
Results
In total, 1232 differentially expressed transcripts were detected after 211At administration,
demonstrating a profound effect on gene regulation. The number of regulated transcripts
increased with higher initial dose-rate/absorbed dose at 1 or 6 h. However, the number of
regulated transcripts decreased with mean absorbed dose/time after 1.7 kBq 211At administration. Furthermore, similar regulation profiles were seen for groups administered
1.7 kBq. Interestingly, few previously proposed radiation responsive genes were detected
in the present study. Regulation of immunological processes were prevalent at 1, 6, and
168 h after 1.7 kBq administration (0.023, 0.32, 1.8 Gy).
Thesis Chapters by J. Spetz
The aim of this work was to study the possibilities to optimize the therapeutic effects of 177Lu-octreotate in the GOT1 model in nude mice.
A literature study of available data on radiolabeled somatostatin analogs on NETs in animal models was performed, to identify strategies for treatment optimization. To test these strategies, GOT1-bearing BALB/c nude mice were treated with non-curative amounts of 177Lu-octreotate in different treatment schedules including single administrations, priming (fractionated) administrations and combination treatment with hedgehog inhibitor sonidegib. Biodistribution and dosimetry studies were performed and anti-tumor effects were monitored by measuring tumor volume. Global transcriptional and proteomic responses in tumor samples were evaluated using RNA microarray and liquid chromatography mass spectrometry, respectively.
177Lu-octreotate therapy of GOT1 tumors xenotransplanted in nude mice resulted in tumor volume reduction. Priming administration resulted in increased anti-tumor effects and increased therapeutic window. Combination therapy using sonidegib and 177Lu-octreotate resulted in prolonged time to progression. The global transcriptional and proteomic analyses of 177Lu-octreotate treated tumor samples revealed time-specific responses in terms of affected biological functions.
In conclusion, time-dependent changes in p53-related cell cycle regulation and apoptosis, angiogenesis, endoplasmic reticulum stress, and oxidative stress-related processes suggest possible niches for combination therapy at different time-points after radionuclide therapy. Priming 177Lu-octreotate therapy and combination therapy using sonidegib and 177Lu-octreotate could be beneficial to patients with NE-tumors.
211At-labeled radiopharmaceuticals are potentially useful for tumor therapy. However, a limitation
has been the preferential accumulation of released 211At in the thyroid gland, which
is a critical organ for such therapy. The aim of this study was to determine the effect of
absorbed dose, dose-rate, and time after 211At exposure on genome-wide transcriptional
expression in mouse thyroid gland.
Methods
BALB/c mice were i.v. injected with 1.7, 7.5 or 100 kBq 211At. Animals injected with 1.7 kBq
were killed after 1, 6, or 168 h with mean thyroid absorbed doses of 0.023, 0.32, and 1.8 Gy,
respectively. Animals injected with 7.5 and 100 kBq were killed after 6 and 1 h, respectively;
mean thyroid absorbed dose was 1.4 Gy. Total RNA was extracted from pooled thyroids
and the Illumina RNA microarray platform was used to determine mRNA levels. Differentially
expressed transcripts and enriched GO terms were determined with adjusted p-value
<0.01 and fold change >1.5, and p-value <0.05, respectively.
Results
In total, 1232 differentially expressed transcripts were detected after 211At administration,
demonstrating a profound effect on gene regulation. The number of regulated transcripts
increased with higher initial dose-rate/absorbed dose at 1 or 6 h. However, the number of
regulated transcripts decreased with mean absorbed dose/time after 1.7 kBq 211At administration. Furthermore, similar regulation profiles were seen for groups administered
1.7 kBq. Interestingly, few previously proposed radiation responsive genes were detected
in the present study. Regulation of immunological processes were prevalent at 1, 6, and
168 h after 1.7 kBq administration (0.023, 0.32, 1.8 Gy).
The aim of this work was to study the possibilities to optimize the therapeutic effects of 177Lu-octreotate in the GOT1 model in nude mice.
A literature study of available data on radiolabeled somatostatin analogs on NETs in animal models was performed, to identify strategies for treatment optimization. To test these strategies, GOT1-bearing BALB/c nude mice were treated with non-curative amounts of 177Lu-octreotate in different treatment schedules including single administrations, priming (fractionated) administrations and combination treatment with hedgehog inhibitor sonidegib. Biodistribution and dosimetry studies were performed and anti-tumor effects were monitored by measuring tumor volume. Global transcriptional and proteomic responses in tumor samples were evaluated using RNA microarray and liquid chromatography mass spectrometry, respectively.
177Lu-octreotate therapy of GOT1 tumors xenotransplanted in nude mice resulted in tumor volume reduction. Priming administration resulted in increased anti-tumor effects and increased therapeutic window. Combination therapy using sonidegib and 177Lu-octreotate resulted in prolonged time to progression. The global transcriptional and proteomic analyses of 177Lu-octreotate treated tumor samples revealed time-specific responses in terms of affected biological functions.
In conclusion, time-dependent changes in p53-related cell cycle regulation and apoptosis, angiogenesis, endoplasmic reticulum stress, and oxidative stress-related processes suggest possible niches for combination therapy at different time-points after radionuclide therapy. Priming 177Lu-octreotate therapy and combination therapy using sonidegib and 177Lu-octreotate could be beneficial to patients with NE-tumors.