sutures newsletter


P & T Approvals; FDA Warns About Zydelig

Pharmacy Focus

See highlights of the February meeting of the Pharmacy and Therapeutics Committee. Also, the U.S. Food and Drug Administration is alerting healthcare professionals about reports of an increased rate of adverse events, including deaths, in clinical trials with the cancer medicine Zydelig in combination with other cancer medicines.

Mark Your Calendar

Surgery Grand Rounds

Click the "read more" to see information about upcoming Surgery Grand Rounds.

Grand Rounds

Click here to view a schedule of all upcoming grand rounds.

Education Schedule

Click the PDF link below to see the Department of Surgery's education schedule.

Education Schedule - March 2016  

Surgery Scheduling

Click the "read more" for hours and contact information for surgery scheduling.

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Obesity and Prostate Cancer - Bedside to Bench and Back

New faculty recruits have joined the lab of Stephen Freedland, MD. Freedland's group specializes in prostate cancer prevention, management and outcomes. Freedland is a surgeon scientist, with a basic science laboratory funded by the National Institutes of Health, who created a research group that studies prostate cancer from the bedside to the laboratory and back again.

With expertise in epidemiology (Adriana Vidal, PhD), preclinical models (Everardo Macias, PhD) and clinical trials (Freedland), the team works to translate important work to the patients as quickly as possible.

Freedland was recruited to the Division of Urology in the Cedars-Sinai Department of Surgery from Duke University in January 2015. Vidal and Macias joined him at Cedars-Sinai shortly after. His team brings added expertise in prostate cancer — already a great strength at Cedars-Sinai.

In addition, Freedland is the founding director of the Center for Integrated Research on Cancer and Lifestyle (CIRCL). The aim of the CIRCL is to further the understanding of how lifestyle factors (diet, exercise, smoking, drinking) impact cancer risk and progression. Using the same "bedside to bench and back again" philosophy, the CIRCL has already opened its first clinical trial for men with recurrent prostate cancer with a second trial opening soon for men with metastatic disease.

It is anticipated that these will be the first of many investigator-initiated studies using a lifestyle intervention aimed at reducing the morbidity and mortality of people with cancer. An overview of Freedland's team research is detailed below.

Inflammation, Prostate Cancer Have Complex Relationship

By Adriana Vidal, PhD, Everardo Macias, PhD, and Stephen Freedland, MD

We have previously shown in multiple publications that obese men are more likely to have aggressive prostate cancer, including progression after surgery. One of the mechanisms through which obesity may increase prostate cancer risk is inflammation. Indeed, it has been postulated that inflammation promotes prostate cancer development.

We and others found aspirin and nonsteroidal anti-inflammatory drugs (e.g., ibuprofen) were linked with lower prostate cancer risk. However, the link between inflammation and prostate cancer is more complex. We previously studied prostate-specific antigen (PSA) levels in healthy men (a potential sign of prostate cancer), and found that while some inflammatory markers were linked with higher PSA levels, others were linked with lower PSA levels, suggesting certain inflammatory markers may be linked with lower prostate cancer risk.

Consistent with this, we studied men who all had prostate biopsies showing no cancer enrolled in a trial for a drug to prevent prostate cancer. The presence of acute and chronic inflammation in the biopsy slides was linked with a 35-40 percent lower risk of prostate cancer on a study-mandated biopsy two years later. The challenge is that while many studies look at inflammation, few dig deep and study the cell types that make up inflammation and when they do, results are interesting.

For example, macrophages — a type of white blood cell — can be divided into M1 and M2. A study found M1 macrophages were more common in early stage prostate cancer, while M2 was more common in advanced disease, suggesting inflammation may promote or prevent prostate cancer, depending on the cell type analyzed. Thus, we are now performing the first in-depth analysis of tissue inflammatory markers, which will allow us to characterize the specific inflammatory cell types present in the prostates of men with and without prostate cancer.

Particularly, we will investigate whether race modifies the associations between inflammatory markers and prostate cancer risk, given that inflammation varies by race and black men have a 67 percent higher prostate cancer risk than white men and over twice the mortality. Beyond the clinical aspects, identifying racial disparities in these tissue markers and importantly which aspects of race drive these differences (socioeconomics, lifestyle, genetics or other factor of "race") provides key mechanistic insights into prostate cancer racial disparity and identifies targets for future studies to modulate these factors to rebalance the inflammatory response to favor anti-prostate cancer inflammation, thus reducing the excess burden of prostate cancer among black men.

Preclinical animal studies from our group and others consistently show that obesity enhances prostate cancer growth. This creates an opportunity for us to exploit the link between obesity and prostate cancer growth to identify and target drivers of aggressive disease. In contrast, dietary interventions, either global calorie restriction or macronutrient deprivation (i.e., carbohydrate or cholesterol restriction) consistently slows tumor growth in mice. However, calorie restriction and macronutrient deprivation only leads to a modest tumor response.

This suggests that there must be either intrinsic or acquired resistance mechanisms that allow tumor cells to continue to survive or even proliferate. One of our objectives is to identify proteins that can be targeted by small molecule inhibitors to decrease obesity associated prostate cancer risks and others that will enhance the anti-tumoral efficacy of dietary interventions. To this end, we are using a genomic screen in mice to identify molecular targets that:

  • Drive prostate cell growth in obese hosts
  • Are essential for survival of prostate cancer cells under calorie restricted conditions

In preliminary studies, our screening has already identified several proteins known to be involved in obesity driven prostate cancer and those that impart resistance to calorie restriction, including Insulin Receptor, IGF-1R, Akt and mTOR, supporting the idea that our genomic screen works. We are currently investigating the therapeutic potential of other candidates from our genomic screen that have not been widely investigated nor targeted in prostate cancer.

Beyond observational studies and animal work, our group is heavily engaged in clinical trials. As noted, prior work from our group has shown that obesity is correlated with more aggressive prostate cancer and a low-carbohydrate diet in mice slows prostate cancer growth. Whether similar effects occur in humans is unknown.

To prepare to answer this question, we first completed a small study testing whether we could get men to adhere to our diet. We randomized men initiating hormonal therapy for prostate cancer to a six-month low-carbohydrate dietary intervention or no intervention. We found that men who were randomized to the low-carbohydrate diet lost 23 pounds.

Thus, given that men would adhere and stick to the diet, the next question we aim to answer is whether such a degree of weight loss will slow cancer growth. To test this, we are randomizing 60 men with recurrent prostate cancer to a low-carbohydrate diet or no diet control and assessing the rate of rise of serum PSA levels. Slower rates of PSA rise are correlated with slowed prostate cancer growth. Thus, we will for the first time test whether a low-carbohydrate diet can slow prostate cancer growth in humans. It is hoped trials such as this will help identify the optimal lifestyle for our cancer patients.

It is this bedside-to bench and back-again approach that drives our research. Together with old collaborators and new ones here at Cedars-Sinai, we aim to ultimately make a difference in how we manage patients.