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NEW ORLEANS – Oxytocin shows promise as a weight-loss medication, with encouraging results in animal models and small human studies. Now, new imaging results show that the hormone inhibits food-related reward circuitry in the brain, tackling the hedonic, nonnutritive eating that can contribute to overweight and obesity in a calorie-rich environment.

“It is clear by now that obesity is a very serious health concern,” Liya Kerem, MD, said in a video interview at the annual meeting of the Endocrine Society. “The most adopted strategy, which is lifestyle modification, does not help [with losing or maintaining] weight in many cases, so we really need to find new treatments for obesity.”

Functional magnetic resonance imaging (fMRI) is a good tool for investigating the neurobiologic basis of overeating, said Dr. Kerem, a pediatric endocrinology fellow at Massachusetts General Hospital, Boston. In previous studies, fMRI has shown that “individuals with obesity have hyperactivation of the reward circuitry in the brain.”

Oxytocin is produced in the hypothalamus and is active in many brain areas associated with reward processing, said Dr. Kerem. Animal studies have shown a decrease in food intake and weight gain with oxytocin administration.

The hormone, which is generally seen as very safe, has had limited study in humans as a weight-loss strategy. Findings from one small study have shown that in men, a single intranasal dose of 24 IU of oxytocin resulted in less hunger-driven eating as well as lower consumption of a postmeal palatable snack, with the latter representing hedonic eating, said Dr. Kerem. A second small pilot study showed that significant weight loss occurred in obese humans after 8 weeks of daily oxytocin administration.

Findings from another study showed that participants who were overweight or obese, unlike their normal-weight counterparts, had reduced activation in the ventral tegmental area (VTA) after oxytocin administration. The VTA is an important region in the brain’s reward network, explained Dr. Kerem.

She and her colleagues used fMRI to probe dynamic changes in brain reward circuitry under the effect of oxytocin. They wanted to understand how oxytocin would “change the dialog between the VTA and the key brain areas involved in processing visual food stimuli.”

The hypothesis was that oxytocin would reduce functional connectivity between the VTA and other brain areas that are important for food reward and sensory processing when the participants were exposed to pictures of high-calorie food.

To test that hypothesis, the researchers showed the participants 100 each of four different kinds of images: high-calorie foods, low-calorie foods, nonfood images, and “fixation” images, used for calibration. The 10 participants had a mean body mass index of 29 kg/m², and the mean age was 31 years.

Oxytocin did indeed attenuate functional connectivity between the VTA and several brain regions that are “key food motivation areas,” said Dr. Kerem. In particular, connections between the VTA and the insula were reduced with oxytocin. The insula is the “gustatory hub of the brain, key to subjective perception of food stimuli,” she explained.

Other attenuated associations included the oral area of the somatosensory cortex; the operculum, which shows fMRI activation to taste; the temporal gyrus, which is important for sensory processing; and, importantly, both the amygdala and hippocampus, known to be important for stimulus-reward learning, said Dr. Kerem. “We found that oxytocin targets exactly that hyperactivation in an overweight and obese population.”

It “reduced the functional connectivity between the VTA, a key hedonic brain region that drives efforts to obtain desired foods, and multiple brain areas involved in the cognitive, sensory, and emotional processing of food cues in men with overweight and obesity,” she said at a press conference highlighting the research. She emphasized that the effect was seen only with exposure to high-calorie food images. “Targeting hyperactivation of reward areas with oxytocin may inhibit overeating behavior,” she added.

Dr. Kerem and her colleagues are currently enrolling men and women for a larger clinical trial of oxytocin for weight loss.

Dr. Kerem reported no conflicts of interest. One of the study’s coauthors is a consultant for OXT Therapeutics, which is investigating obesity-related uses for oxytocin.

[email protected]

NEW ORLEANS – Oxytocin shows promise as a weight-loss medication, with encouraging results in animal models and small human studies. Now, new imaging results show that the hormone inhibits food-related reward circuitry in the brain, tackling the hedonic, nonnutritive eating that can contribute to overweight and obesity in a calorie-rich environment.

“It is clear by now that obesity is a very serious health concern,” Liya Kerem, MD, said in a video interview at the annual meeting of the Endocrine Society. “The most adopted strategy, which is lifestyle modification, does not help [with losing or maintaining] weight in many cases, so we really need to find new treatments for obesity.”

Functional magnetic resonance imaging (fMRI) is a good tool for investigating the neurobiologic basis of overeating, said Dr. Kerem, a pediatric endocrinology fellow at Massachusetts General Hospital, Boston. In previous studies, fMRI has shown that “individuals with obesity have hyperactivation of the reward circuitry in the brain.”

Oxytocin is produced in the hypothalamus and is active in many brain areas associated with reward processing, said Dr. Kerem. Animal studies have shown a decrease in food intake and weight gain with oxytocin administration.

The hormone, which is generally seen as very safe, has had limited study in humans as a weight-loss strategy. Findings from one small study have shown that in men, a single intranasal dose of 24 IU of oxytocin resulted in less hunger-driven eating as well as lower consumption of a postmeal palatable snack, with the latter representing hedonic eating, said Dr. Kerem. A second small pilot study showed that significant weight loss occurred in obese humans after 8 weeks of daily oxytocin administration.

Findings from another study showed that participants who were overweight or obese, unlike their normal-weight counterparts, had reduced activation in the ventral tegmental area (VTA) after oxytocin administration. The VTA is an important region in the brain’s reward network, explained Dr. Kerem.

She and her colleagues used fMRI to probe dynamic changes in brain reward circuitry under the effect of oxytocin. They wanted to understand how oxytocin would “change the dialog between the VTA and the key brain areas involved in processing visual food stimuli.”

The hypothesis was that oxytocin would reduce functional connectivity between the VTA and other brain areas that are important for food reward and sensory processing when the participants were exposed to pictures of high-calorie food.

To test that hypothesis, the researchers showed the participants 100 each of four different kinds of images: high-calorie foods, low-calorie foods, nonfood images, and “fixation” images, used for calibration. The 10 participants had a mean body mass index of 29 kg/m², and the mean age was 31 years.

Oxytocin did indeed attenuate functional connectivity between the VTA and several brain regions that are “key food motivation areas,” said Dr. Kerem. In particular, connections between the VTA and the insula were reduced with oxytocin. The insula is the “gustatory hub of the brain, key to subjective perception of food stimuli,” she explained.

Other attenuated associations included the oral area of the somatosensory cortex; the operculum, which shows fMRI activation to taste; the temporal gyrus, which is important for sensory processing; and, importantly, both the amygdala and hippocampus, known to be important for stimulus-reward learning, said Dr. Kerem. “We found that oxytocin targets exactly that hyperactivation in an overweight and obese population.”

It “reduced the functional connectivity between the VTA, a key hedonic brain region that drives efforts to obtain desired foods, and multiple brain areas involved in the cognitive, sensory, and emotional processing of food cues in men with overweight and obesity,” she said at a press conference highlighting the research. She emphasized that the effect was seen only with exposure to high-calorie food images. “Targeting hyperactivation of reward areas with oxytocin may inhibit overeating behavior,” she added.

Dr. Kerem and her colleagues are currently enrolling men and women for a larger clinical trial of oxytocin for weight loss.

Dr. Kerem reported no conflicts of interest. One of the study’s coauthors is a consultant for OXT Therapeutics, which is investigating obesity-related uses for oxytocin.

[email protected]

NEW ORLEANS – Oxytocin shows promise as a weight-loss medication, with encouraging results in animal models and small human studies. Now, new imaging results show that the hormone inhibits food-related reward circuitry in the brain, tackling the hedonic, nonnutritive eating that can contribute to overweight and obesity in a calorie-rich environment.

“It is clear by now that obesity is a very serious health concern,” Liya Kerem, MD, said in a video interview at the annual meeting of the Endocrine Society. “The most adopted strategy, which is lifestyle modification, does not help [with losing or maintaining] weight in many cases, so we really need to find new treatments for obesity.”

Functional magnetic resonance imaging (fMRI) is a good tool for investigating the neurobiologic basis of overeating, said Dr. Kerem, a pediatric endocrinology fellow at Massachusetts General Hospital, Boston. In previous studies, fMRI has shown that “individuals with obesity have hyperactivation of the reward circuitry in the brain.”

Oxytocin is produced in the hypothalamus and is active in many brain areas associated with reward processing, said Dr. Kerem. Animal studies have shown a decrease in food intake and weight gain with oxytocin administration.

The hormone, which is generally seen as very safe, has had limited study in humans as a weight-loss strategy. Findings from one small study have shown that in men, a single intranasal dose of 24 IU of oxytocin resulted in less hunger-driven eating as well as lower consumption of a postmeal palatable snack, with the latter representing hedonic eating, said Dr. Kerem. A second small pilot study showed that significant weight loss occurred in obese humans after 8 weeks of daily oxytocin administration.

Findings from another study showed that participants who were overweight or obese, unlike their normal-weight counterparts, had reduced activation in the ventral tegmental area (VTA) after oxytocin administration. The VTA is an important region in the brain’s reward network, explained Dr. Kerem.

She and her colleagues used fMRI to probe dynamic changes in brain reward circuitry under the effect of oxytocin. They wanted to understand how oxytocin would “change the dialog between the VTA and the key brain areas involved in processing visual food stimuli.”

The hypothesis was that oxytocin would reduce functional connectivity between the VTA and other brain areas that are important for food reward and sensory processing when the participants were exposed to pictures of high-calorie food.

To test that hypothesis, the researchers showed the participants 100 each of four different kinds of images: high-calorie foods, low-calorie foods, nonfood images, and “fixation” images, used for calibration. The 10 participants had a mean body mass index of 29 kg/m², and the mean age was 31 years.

Oxytocin did indeed attenuate functional connectivity between the VTA and several brain regions that are “key food motivation areas,” said Dr. Kerem. In particular, connections between the VTA and the insula were reduced with oxytocin. The insula is the “gustatory hub of the brain, key to subjective perception of food stimuli,” she explained.

Other attenuated associations included the oral area of the somatosensory cortex; the operculum, which shows fMRI activation to taste; the temporal gyrus, which is important for sensory processing; and, importantly, both the amygdala and hippocampus, known to be important for stimulus-reward learning, said Dr. Kerem. “We found that oxytocin targets exactly that hyperactivation in an overweight and obese population.”

It “reduced the functional connectivity between the VTA, a key hedonic brain region that drives efforts to obtain desired foods, and multiple brain areas involved in the cognitive, sensory, and emotional processing of food cues in men with overweight and obesity,” she said at a press conference highlighting the research. She emphasized that the effect was seen only with exposure to high-calorie food images. “Targeting hyperactivation of reward areas with oxytocin may inhibit overeating behavior,” she added.

Dr. Kerem and her colleagues are currently enrolling men and women for a larger clinical trial of oxytocin for weight loss.

Dr. Kerem reported no conflicts of interest. One of the study’s coauthors is a consultant for OXT Therapeutics, which is investigating obesity-related uses for oxytocin.

[email protected]

ATLANTA – Lynch syndrome serves as an excellent platform for the development of immunoprevention cancer vaccines, and findings from a preclinical Lynch syndrome mouse model support ongoing research, according to Steven M. Lipkin, MD, PhD.

A novel vaccine, which included peptides encoding four intestinal cancer frameshift peptide (FSP) neoantigens derived from coding microsatellite (cMS) mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses in the model, Dr. Lipkin, the Gladys and Roland Harriman Professor of Medicine and vice chair for research in the Sanford and Joan Weill Department of Medicine, Weill Cornell Medical College, New York, reported at the annual meeting of the American Association for Cancer Research.

CD4-specific T cell responses were detected for Maz, Nacad, and Senp6, and CD8-positive T cells were detected for Xirp1 and Nacad, he noted, explaining that the findings come in the wake of a recently completed clinical phase 1/2a trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in microsatellite unstable (MSI) colorectal cancer patients.

The current effort to further develop a cancer preventive vaccine against MSI cancers in Lynch syndrome using a preclinical mouse model involved a systematic database search to identify cMS sequences in the murine genome. Intestinal tumors obtained from Lynch syndrome mice were evaluated for mutations affecting these candidate cMS, and of 13 with a mutation frequency of 15% or higher, the 4 FSP neoantigens ultimately included in the vaccine elicited strong antigen-specific cellular immune responses.

Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted antineoantigen immunity, reduced intestinal tumorigenicity, and prolonged overall survival, Dr. Lipkin said.

Further, based on preclinical data suggesting that naproxen in this setting might provide better risk-reducing effects, compared with aspirin (which has previously been shown to reduce colorectal cancer risk in Lynch syndrome patients), its addition to the vaccine did, indeed, improve response, he noted, explaining that naproxen worked as “sort of a super-aspirin,” that improved overall survival, compared with vaccine alone or nonsteroidal anti-inflammatory agents alone.

In a video interview, Dr. Lipkin describes his research and its potential implications for the immunoprevention of Lynch syndrome and other cancers.

Vaccination with as few as four mutations that occur across Lynch syndrome tumors induced complete cures in some mice and delays in disease onset in others, he said.

“[This is] a very simple approach, very effective,” he added, noting that the T cells are now being studied to better understand the biology of the effects. “The idea of immunoprevention ... is actually very exciting and ... can be expanded beyond this.”

Lynch syndrome is a “great place to start,” because of the high rate of mutations, which are the most immunogenic types of mutations, he said.

“If we can get this basic paradigm to work, I think we can expand it to other types of mutations – for example, KRAS or BRAF, which are seen frequently in lung cancers, colon cancers, stomach cancers, pancreatic cancers, and others,” he said, noting that a proposal for a phase 1 clinical trial has been submitted.
 

ATLANTA – Lynch syndrome serves as an excellent platform for the development of immunoprevention cancer vaccines, and findings from a preclinical Lynch syndrome mouse model support ongoing research, according to Steven M. Lipkin, MD, PhD.

A novel vaccine, which included peptides encoding four intestinal cancer frameshift peptide (FSP) neoantigens derived from coding microsatellite (cMS) mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses in the model, Dr. Lipkin, the Gladys and Roland Harriman Professor of Medicine and vice chair for research in the Sanford and Joan Weill Department of Medicine, Weill Cornell Medical College, New York, reported at the annual meeting of the American Association for Cancer Research.

CD4-specific T cell responses were detected for Maz, Nacad, and Senp6, and CD8-positive T cells were detected for Xirp1 and Nacad, he noted, explaining that the findings come in the wake of a recently completed clinical phase 1/2a trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in microsatellite unstable (MSI) colorectal cancer patients.

The current effort to further develop a cancer preventive vaccine against MSI cancers in Lynch syndrome using a preclinical mouse model involved a systematic database search to identify cMS sequences in the murine genome. Intestinal tumors obtained from Lynch syndrome mice were evaluated for mutations affecting these candidate cMS, and of 13 with a mutation frequency of 15% or higher, the 4 FSP neoantigens ultimately included in the vaccine elicited strong antigen-specific cellular immune responses.

Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted antineoantigen immunity, reduced intestinal tumorigenicity, and prolonged overall survival, Dr. Lipkin said.

Further, based on preclinical data suggesting that naproxen in this setting might provide better risk-reducing effects, compared with aspirin (which has previously been shown to reduce colorectal cancer risk in Lynch syndrome patients), its addition to the vaccine did, indeed, improve response, he noted, explaining that naproxen worked as “sort of a super-aspirin,” that improved overall survival, compared with vaccine alone or nonsteroidal anti-inflammatory agents alone.

In a video interview, Dr. Lipkin describes his research and its potential implications for the immunoprevention of Lynch syndrome and other cancers.

Vaccination with as few as four mutations that occur across Lynch syndrome tumors induced complete cures in some mice and delays in disease onset in others, he said.

“[This is] a very simple approach, very effective,” he added, noting that the T cells are now being studied to better understand the biology of the effects. “The idea of immunoprevention ... is actually very exciting and ... can be expanded beyond this.”

Lynch syndrome is a “great place to start,” because of the high rate of mutations, which are the most immunogenic types of mutations, he said.

“If we can get this basic paradigm to work, I think we can expand it to other types of mutations – for example, KRAS or BRAF, which are seen frequently in lung cancers, colon cancers, stomach cancers, pancreatic cancers, and others,” he said, noting that a proposal for a phase 1 clinical trial has been submitted.
 

ATLANTA – Lynch syndrome serves as an excellent platform for the development of immunoprevention cancer vaccines, and findings from a preclinical Lynch syndrome mouse model support ongoing research, according to Steven M. Lipkin, MD, PhD.

A novel vaccine, which included peptides encoding four intestinal cancer frameshift peptide (FSP) neoantigens derived from coding microsatellite (cMS) mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses in the model, Dr. Lipkin, the Gladys and Roland Harriman Professor of Medicine and vice chair for research in the Sanford and Joan Weill Department of Medicine, Weill Cornell Medical College, New York, reported at the annual meeting of the American Association for Cancer Research.

CD4-specific T cell responses were detected for Maz, Nacad, and Senp6, and CD8-positive T cells were detected for Xirp1 and Nacad, he noted, explaining that the findings come in the wake of a recently completed clinical phase 1/2a trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in microsatellite unstable (MSI) colorectal cancer patients.

The current effort to further develop a cancer preventive vaccine against MSI cancers in Lynch syndrome using a preclinical mouse model involved a systematic database search to identify cMS sequences in the murine genome. Intestinal tumors obtained from Lynch syndrome mice were evaluated for mutations affecting these candidate cMS, and of 13 with a mutation frequency of 15% or higher, the 4 FSP neoantigens ultimately included in the vaccine elicited strong antigen-specific cellular immune responses.

Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted antineoantigen immunity, reduced intestinal tumorigenicity, and prolonged overall survival, Dr. Lipkin said.

Further, based on preclinical data suggesting that naproxen in this setting might provide better risk-reducing effects, compared with aspirin (which has previously been shown to reduce colorectal cancer risk in Lynch syndrome patients), its addition to the vaccine did, indeed, improve response, he noted, explaining that naproxen worked as “sort of a super-aspirin,” that improved overall survival, compared with vaccine alone or nonsteroidal anti-inflammatory agents alone.

In a video interview, Dr. Lipkin describes his research and its potential implications for the immunoprevention of Lynch syndrome and other cancers.

Vaccination with as few as four mutations that occur across Lynch syndrome tumors induced complete cures in some mice and delays in disease onset in others, he said.

“[This is] a very simple approach, very effective,” he added, noting that the T cells are now being studied to better understand the biology of the effects. “The idea of immunoprevention ... is actually very exciting and ... can be expanded beyond this.”

Lynch syndrome is a “great place to start,” because of the high rate of mutations, which are the most immunogenic types of mutations, he said.

“If we can get this basic paradigm to work, I think we can expand it to other types of mutations – for example, KRAS or BRAF, which are seen frequently in lung cancers, colon cancers, stomach cancers, pancreatic cancers, and others,” he said, noting that a proposal for a phase 1 clinical trial has been submitted.
 

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.