Williams Cancer Institute

This certainly may apply to many cancers, as unfortunately, most are immunologically “cold,” which is why the current FDA approved immunotherapies fail in the majority of cases. There are numerous techniques to turn “cold” tumors to “hot.” Among these are injection into a tumor TLR agonist, STING agonist, CD40 agonist, and Oncopore peptides, to name a few. This article discusses using ultrasound to control temperature. The surprising aspect was it was not necessarily heating things up, like hyperthermia, but keeping the temperature stable. A very interesting and unexpected conclusion.

There is also a nice animation explaining the immune response to cancer and how cancer can evade the immune system.

Source: Labroots

Photo: Pixabay

We have discussed this before. It is becoming standard in our patients to not only evaluate the microbiome with Microbiome Dx, but also patients with recent antibiotic use prior to immunotherapy probably will need a fecal microbiota transplant (FMT).

Taking antibiotics in the month before starting immunotherapy dramatically reduces a cancer patient’s chances of survival, according to a small but groundbreaking study.

Scientists at Imperial College London believe antibiotics strip out helpful bacteria from the gut, which weakens the immune system. This appears to make it less likely that immunotherapy drugs will boost the body’s cancer-fighting capability.

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Source : https://amp.theguardian.com/society/2019/sep/12/antibiotic-use-before-cancer-treatment-cuts-survival-time-study?fbclid=IwAR0R9gSLfPW5nh1AKIloHHuYgYM6kFQpt2aEnYV9HZWR15EuVFn31Jg7F9E

Stay tuned for the release of The Immunotherapy Revolution: The Best New Hope For Saving Cancer Patients Lives by the incredible Dr. Jason Williams from the Williams Cancer Institute.

This book is a must read for all cancer patients.

If you are interested in, or are already getting immunotherapy for cancer, this book is your guide to boosting the response and beating cancer.

Breast cancer is one of the most commonly diagnosed cancer types among women globally. Globally, there were an estimated 2.1 million new cases of breast cancer and 630,000 deaths due to breast cancer in 2018. In the United States alone, there were an estimated 270,000 cases of breast cancer diagnosed in 2018 along with 41,000 deaths, and approximately 1 in 8 women and about 1 in 1,000 men will develop invasive breast cancer at some point in their lives. Thus, the need for effective, lasting breast cancer treatment is urgent.

Increased risk for breast cancer is associated with a personal or family history of the disease and inherited genetic mutations in breast cancer susceptibility genes. These include BRCA1 and BRCA2 and other less common inherited gene mutations. An inherited predisposition to develop breast cancer accounts for approximately 5%-10% of all breast cancer cases, but is rare in the general population (less than 1%). Women with BRCA1 and BRCA2 mutations have an estimated 45% to 65% higher risk of developing breast cancer by age 70, though the risk is highest around age 40. People with these mutations should discuss their risk with a genetic counsellor. Other known risk factors include obesity, use of MHT (a hormone therapy that combines progestin and estrogen), high breast tissue density, alcohol consumption, and physical inactivity.

Current methods for breast cancer treatment typically involve surgery if the disease is diagnosed early. Depending on the stage and molecular characteristics of the cancer when diagnosed, breast cancer surgery may be followed by additional chemotherapy, radiation, or targeted therapies, including hormone therapy.

Although breast cancer has long been regarded as difficult to treat with immunotherapy because it is immunologically cold, several newer preclinical and clinical studies now suggest that immunotherapy treatment has the potential to improve outcomes for breast cancer patients.

In March 2019, the FDA approved the first checkpoint inhibitor immunotherapy drug, an anti-PD-L1 antibody called atezolizumab, (Tecentriq®), in combination with chemotherapy, for the treatment of triple-negative, metastatic breast cancer in patients whose tumors express the PD-L1 protein.

Source: https://www.cancerresearch.org/immunotherapy/cancer-types/breast-cancer

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New research from the University of Virginia Cancer Center and recently published in the journal Cancer Research suggests that an unhealthy gut microbiome could result in the spread of breast cancer throughout the body.

The research was spearheaded by Melanie Rutkowski, PhD, of UVA’s Department of Microbiology, Immunology and Cancer Biology. Dr. Rutkowski used mice to show how an unhealthy gut caused breast cancer to become much more aggressive, leading it to disseminate to other parts of the body.

“When we disrupted the microbiome’s equilibrium in mice by chronically treating them antibiotics, it resulted in inflammation systemically and within the mammary tissue,” Dr. Rutkowski explains. “In this inflamed environment, tumor cells were much more able to disseminate from the tissue into the blood and to the lungs, which is a major site for hormone receptor-positive breast cancer to metastasize.”

“Disrupting the microbiome resulted in long-term inflammation within the tissue and the tumor environment, “Rutkowski said.” These findings suggest that having an unhealthy microbiome, and the changes that occur within the tissue that are related to an unhealthy microbiome, may be early predictors of invasive or metastatic breast cancer. Ultimately, based upon these findings, we would speculate that an unhealthy microbiome contributes to increased invasion and a higher incidence of metastatic disease.”

However, Rutkowski is quick to reassure that the use of antibiotics in human women should not be enough to disrupt a women’s microbiome to the extent that she was with the mice in her research. Instead, she says, her methods utilized antibiotics as a means to disrupt the microbiomes of the mice and simulate what an unhealthy biome looks like, so as to determine its influence on the spread of breast cancer. Women with breast cancer should not, she says, refrain using antibiotics if needed to treat an infection just because of her study’s results.

The take-home message from Dr. Rutkowskiâ’s research is how crucial a healthy microbiome is, not just to prevent the spread of breast cancer, but for overall good health.

Source: Labroots

Combination of radiation, chemo, and blood-pressure drug losartan extends patient survival.

Locally advanced pancreatic cancer (LAPC) a tumor that, while still confined to the pancreas, involves major abdominal blood vessels is one of the worst forms of an already deadly tumor, as it cannot be removed surgically. Now a Massachusetts General Hospital (MGH) Cancer Center clinical trial of a treatment protocol combining intensive chemotherapy and radiation with the blood-pressure drug losartan has produced unprecedented results, allowing complete removal of the tumor in 61 percent of participants and significantly improving survival rates.

Around 40 percent of pancreatic cancer patients have either locally advanced or borderline resectable disease, with historically poor rates of successful surgery, said Janet Murphy, an instructor in medicine in the hematology/oncology division of Mass. General’s Department of Medicine, co-lead and corresponding author of the report in JAMA Oncology. To be able to successfully remove the primary tumor in 61 percent of patients sets a new benchmark and offers much hope. To our knowledge, this is the first LAPC clinical trial that defined surgical success as its primary outcome.

The most novel element of the trial use of the antihypertension drug losartan builds on the findings of co-author Rakesh K. Jain, director of the Steele Laboratories for Tumor Biology at MGH and Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School, and his colleagues. Those studies found that losartan, which targets the angiotensin signaling pathway, improved the delivery of chemotherapy drugs in animal models of breast, pancreatic, and ovarian cancer. It does so by relieving pressures in the tumor microenvironment that physically block drug delivery and reduce the supply of oxygen, which is required for the tumor-killing effects of radiation therapy. Those studies also found that cancer patients who happened to be taking losartan or similar drugs for hypertension tended to live longer than others receiving the same sorts of cancer therapies.

From August 2013 through July 2017 the study enrolled 49 MGH Cancer Center patients with previously untreated LAPC. All participants received chemotherapy with a combination of fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) over a four-month period, during which they also took daily doses of losartan. After CT scan evaluation to determine whether blood vessels were still involved in the tumors, patients who no longer had vascular involvement received a short course of proton-beam radiation therapy, while those whose tumors still included major blood vessels had a longer course of conventional radiation therapy. Both groups received capecitabine chemotherapy during this period.

After completing the chemoradiotherapy stage, 34 of the 49 participants were able to have their tumors removed, with 30 of those procedures successfully eliminating all evidence of cancer around the tumor. A pathologic complete response which signifies no tumor found anywhere was achieved for three patients. Analysis of circulating biomarkers throughout the course of the study found significant drops in the expression of TGF-β, a key element in the angiotensin-signaling pathway, indicating that losartan was having its desired effect. Both the time until recurrence and the overall survival time were significantly longer than what previously had been seen in LAPC patients.

A key part of the success of our approach was our surgeons willingness to attempt an operation even in patients who had the appearance of cancer at or near their blood vessels, said Murphy. We learned in a previous study, confirmed here, that CT scan results and resectability are no longer clearly correlated after chemotherapy and radiation. While we did not see total blood vessel clearance in 61 percent of patients, 61 percent achieved a complete removal of their cancer.

lead author Jennifer Wo, an assistant professor of radiation oncology, adds, Locally advanced pancreatic cancer has been generally considered an incurable disease, so these results mark a dramatic improvement with respect both to rates of conversion to surgical resectability and to long-term disease outcomes. Based on these results we have launched a new, multi-institutional clinical trial that will also include the immunotherapy drug nivolumab, since losartan treatment has also been shown to activate several immune-system pathways.

The co-senior authors of this report are Theodore Hong, MGH Radiation Oncology, and Carlos Fernández-del Castillo, MGH Department of Surgery.

Resources: https://news.harvard.edu/gazette/story/2019/05/mass-general-trial-shows-novel-protocol-improves-pancreatic-cancer-outcomes/?fbclid=IwAR3YSzZDHBIxFP9R4myontRlp4VCG4gjuEuOP0C3lvt09CTYlct5A8xiiuM

A new approach to breast cancer may prevent cancer from reappearing years later.

They got all of it are the reassuring words people hope to hear following cancer surgery, but a growing understanding of the science of how cancer spreads, and metastasizes, is suggesting that not only is this almost never true but and here is the surprising part it might be better to try to contain the cancer than to eliminate it.

The new approach, which at this point has been tested only in animal models, is called “Lock-‘n’-block” and a national team of scientists led by researchers at Purdue University has found that a drug already on the market for another use is showing strong promise as a therapy to keep breast cancer from metastasizing.

Michael Wendt, assistant professor of medicinal chemistry and molecular pharmacology, says that cancer researchers are beginning to realize they have been chasing an impossible goal.

Most cancer therapy is targeted with the idea that we want to kill all of the cancer cells. Rid the body of cancer. But recently, there are lots of studies that suggest that we’re never going to be able to do that. Cancer cells evolve so fast that they will always find a way to overcome any type of therapy Wendt said. An emerging concept in cancer treatment is that maybe we shouldn’t try to kill all of the cancer cells, but try to keep them in a low state that doesn’t generate any kind of symptoms. A sort of dormancy, if you will.

Wendt has led a multi-institutional study that has identified a drug fostamatinib, which is sold under the trade name Tavalisse that was shown to be effective in mice in blocking and containing metastatic cancer cells. The research was recently published in the journal Cancer Research.

Aparna Shinde, a researcher at AbbVie Inc., and formerly a graduate student in the Purdue’s Department of Medicinal Chemistry and Molecular Pharmacology, said the research focused on breast cancer because it is especially known to lead to metatisizing cancers years later.

After you have breast cancer you always get this dissemination of cancer cells, she said. Breast cancer is no longer considered a curable disease it is now considered a chronic disease, because 10 or 20 years later, you can get secondary tumors because of the metastasizing cells.

But now we have shown that we can block these cells in a dormant state so that even if a patient has these metastizing cells we can hold them in this state for a very long time.

Wendt explains that when cancer cells move from a primary tumor and go to another part of the body, they can go through some form of years-long dormancy or latency. These cancer cells are very resistant to current drug therapies, because current drugs are designed to target cells that grow faster than normal cells, as tumor cells do. That is not true of these disseminated cancer cells, which can lie dormant for many, many years.

So that’s the goal we are exploring now. Instead of trying to eliminate those disseminated cells, how do we keep them in that dormant state? Wendt said.

The researchers used the drug fostamatinib because it inhibits a particular protein, spleen tyrosine kinase (SYK), that is found in these disseminated cancer cells.

This is great for us because this is a drug with low toxicity. It’s designed for people with chronic disease so that they can take for a long time, Wendt said. So, we think fostamatinib is a perfect candidate for this kind of years-long “Lock-‘n’-block” type of approach. We think this is a good candidate to move forward for a trial to see if we can stabilize dormancy. If SYK is expressed in other cancers this could apply to those as well.

In their current study, the researchers removed breast cancer tumors from the mice surgically. The tumor cells were labeled with luciferase, the bioluminescent firefly protein, which allows the researchers to track and quantify the level of metatisizing cells.

The researchers found that the cancer cells treated with fostamatinib remained in a dormant state and did not cause metastases in other areas of the body.

Our work is unique because there hasn’t been much research that tests treatments in a post-surgical metastatic setting. Most research is focused on treating the primary tumor. We are looking to target the later processes of disease to see if we can hold tumor cells in their dormant state, Wendt said. But you can imagine that clinical trials for this kind of thing is going to be very difficult because technically the patients are in remission and disease-free. We suspect that these patients have these dormant cancer cells disseminating through their bodies, but we don’t have a way to detect those right now.

Source: https://medicalxpress.com/news/2019-04-lock-n-block-drug-cancer-metastasizing.html?fbclid=IwAR18tygFU20g3OHiCSXp5BXcFsRAyEt-C1q7n3ASXRXagEhbsXJqc1xYOnA