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Breast Cancer Drug Resistance Linked to Diet High in Leucine

Breast Cancer Drug Resistance Linked to Diet High in Leucine

Researchers at the Beth Israel Deaconess Medical Center (BIDMC) Cancer Center have uncovered an unexpected link between the essential amino acid leucine and tamoxifen resistance in estrogen-receptor positive (ER+) breast cancer, which hint that patients may benefit from reducing how much animal protein they eat. Studies headed by Senthil K. Muthuswamy, PhD, and colleagues, in cultured cells and in mice, indicated that reducing leucine levels suppresses ER+ breast cancer cell proliferation, and showed that a key leucine carrier that is responsible for importing the amino acid into cells acts to regulate response to tamoxifen.

“Our findings in the lab demonstrate that decreasing leucine levels suppresses proliferation of tumor cells, whereas increasing leucine enhances it,” commented Muthuswamy, who is director of the cell biology program and deputy director of translational research in the Cancer Research Institute at BIDMC. “Furthermore, the findings open up the possibility that a low-leucine diet could be beneficial for patients with ER+ breast cancer … Because animal proteins have a higher amount of leucine compared to plant proteins, this study begins to identify a diet intervention strategy to help patients with ER+ breast cancers.”

The team reported its findings in Nature, in a paper titled, “LLGL2 rescues nutrient stress by promoting leucine uptake in ER+ breast cancer.”

About one in eight women will develop breast cancer, and about 75% of cases are estrogen receptor positive cancers that need estrogen and/or progesterone to grow. This type of cancer is commonly treated using the endocrine therapy tamoxifen, which attaches to the hormone receptor in the cancer cells, blocking estrogen from binding. However, the treatment will frequently stop working as the cancer cells become tamoxifen resistant. “… the development of resistance to endocrine therapy and metastatic progression are leading causes of death for patients with ER+ disease,” the authors wrote. “Patients with ER+ breast cancer who develop endocrine-resistant and metastatic cancer have very poor life expectancy, usually less than five years survival, because they have limited treatment options available,” Muthuswamy noted.

The proteins in our bodies are made up of 20 amino acid building blocks. Nine of these amino acids, including leucine, are known as essential amino acids because our cells can’t make them from scratch, and so we have to obtain them from our food. Meat and fish are particularly rich sources of leucine.

Muthuswamy’s team manipulated leucine levels in cultures of ER+ breast cancer cells to see how cell growth would be affected. They found that reducing leucine held back ER+ breast cancer cell division, while increasing leucine levels tenfold increased cell proliferation. The researchers also found that cells that had been induced to become resistant to tamoxifen could still proliferate even when levels of leucine were low. Further studies showed that the tamoxifen-resistant cells carried high levels of the leucine transporter SCL7A5 (also referred to as LAT1 (L-type amino acid transporter), a cell surface protein that carries the amino acid into cells. Increasing levels of SLC7A5 in cultured ER+ MCF-7 breast cancer cells effectively allowed the cells to acquire more leucine, and their resistance to tamoxifen increased. “Strikingly, overexpression of SLC7A5 in parental MCF-7 cells was sufficient to induce tamoxifen resistance,” the investigators noted. Conversely, chemically inhibiting SLC7A5 led to ER+ tumor in live mouse models.

Interestingly, the researchers wrote, SLC7A5 is overexpressed in multiple cancers, including breast cancer. An analysis of patient data showed that high expression of SLC7A5 “correlated with poor survival in 799 patients with ER+ breast cancer who had been treated with tamoxifen,” they commented. The BIDMC findings that SLC7A5 is necessary for and also sufficient to confer resistance to tamoxifen therapy have highlighted SLC7A5 as “a potential therapeutic target for overcoming resistance to endocrine treatments in breast cancer.”

Senthil K. Muthuswamy, PhD, of the Cancer Center at Beth Israel Deaconess Medical Center. [BIDMC]

The reported results also offer up completely new insights into tumor cell biology, the researchers noted, and indicate that cells adapt to nutrient stress by increasing surface SLC7A5. “Before this research, there was no reason to expect that estrogen biology has anything to do with affecting intracellular levels of leucine in cells,” said first author, Yasuhiro Saito, PhD, a research fellow in the department of medicine and pathology at BIDMC. “We have uncovered a new area of estrogen receptor biology, which will lead to new strategies to help patients with endocrine-resistant breast cancer.”

Prior research has reported that reducing intake of leucine can improve metabolic health, Muthuswamy noted. Decreasing total dietary protein has also been linked with better metabolic health and lifespan in rodent studies, while human and mouse studies have demonstrated that a low leucine diet can have health benefits. Although restricting protein intake to the point that it doesn’t meet daily nutrient requirements is not advisable, Muthuswamy suggested that a diet made-up of low-leucine plant proteins may be a better alternative for patients with ER+ breast cancer.

The researchers are not suggesting that diets high in leucine act to fuel breast cancer, Muthuswamy noted. “Our research does not imply that animal proteins will enhance growth of breast cancer cells—only that lowering leucine levels can be beneficial for patients diagnosed with ER+ breast cancer … A properly controlled clinical study to assess clinical benefit of actively decreasing leucine intake in diet during treatment for ER+ breast cancer will be of significant value because a positive outcome can provide a simple intervention strategy that can help us better care for patients with endocrine-sensitive and resistant breast cancer.”

The BIDMC team is already investigating whether a diet low in leucine can help to prevent ER+ tumor growth or boost response to therapy in mouse models.



The post Breast Cancer Drug Resistance Linked to Diet High in Leucine appeared first on GEN – Genetic Engineering and Biotechnology News.

Source: Genengnews

Scientists identify a novel target for corn straw utilization

Scientists identify a novel target for corn straw utilization
Plant cell walls, as repositories of fixed carbon, are an important source of biomass, which is mainly composed of cellulose, hemicellulose, and lignin. However, the complex lignin structure makes it a rather inefficient biomass source. Thorough understanding of lignin biosynthesis will improve the efficiency of biomass conversion into biofuels and increase the quality of forage and silage.


Synthetic Receptor Can Distinguish Between Male and Female Steroid Hormones

Synthetic Receptor Can Distinguish Between Male and Female Steroid Hormones

oshihisa Sei, Masahiro Yamashina, and Michito Yoshizawa
(From left) Yoshihisa Sei, Masahiro Yamashina, and Michito Yoshizawa in front of x-ray diffractometer for crystallographic analysis. [Michito Yoshizawa]

Scientists at Tokyo Tech’s Laboratory for Chemistry and Life Science report that they have designed and developed a capsule-shaped synthetic receptor that can distinguish between male and female steroid hormones. Namely, the receptor displays unusual high binding affinity toward androgenic male hormones in water.

The researchers envision that their synthetic receptor will be used for the development of practical, ultrasensitive analytical devices for steroid sex hormones, ranging from medical tools to doping controls in sports, in the near future.

The study (“A polyaromatic receptor with high androgen affinity”), published in Science Advances, represents an example of biomimetic design, i.e., the creation of systems that mimic ideas from nature, according to the team. “Natural biological receptors can recognize tiny structural differences between male and female steroid hormones using their protein pockets,” the authors said. “However, it has been challenging to emulate this function artificially until now.”

“Biological receptors distinguish and bind steroid sex hormones, e.g., androgen-, progestogen-, and estrogen-type hormones, with high selectivity. To date, artificial molecular receptors have been unable to discriminate between these classes of biosubstrates. Here, we report that an artificial polyaromatic receptor preferentially binds a single molecule of androgenic hormones, known as ‘male’ hormones (indicated with m), over progestogens and estrogens, known as ‘female’ hormones (indicated with f) in water,” the investigators wrote.

“Competitive experiments established the binding selectivity of the synthetic receptor for various sex hormones to be testosterone (m) > androsterone (m) >> progesterone (f) > β-estradiol (f) > pregnenolone (f) > estriol (f). These bindings are driven by the hydrophobic effect, and the observed selectivity arises from multiple CH-π contacts and hydrogen-bonding interactions in the semirigid polyaromatic cavity. Furthermore, micromolar fluorescence detection of androgen was demonstrated using the receptor containing a fluorescent dye in water.”

The researchers note that the key to their advance was the unique design of the cavity (mimicking the natural pocket but using unnatural components) within the receptor. This cavity, encircled by polyaromatic frameworks held together with metal ions, enabled the receptor to act as a semi-rigid container, one flexible enough to complement the shape of the hormone and to induce effective bonding interactions.

The study, conducted by Michito Yoshizawa, PhD, Masahiro Yamashina, PhD, and co-workers, is a continuation of the team’s previous work on developing nanocapsules for a wide range of biosensing applications in the medical and environmental fields. Their experiments showed that the synthetic receptor preferentially binds steroid sex hormones in an order similar to natural androgen receptors, beginning with male hormones such as testosterone and androsterone, followed by female hormones such as progesterone and beta-estradiol. When placed in a mixture of male and female hormones suspended in an aqueous solution at 60 degrees Celsius for ten minutes, the receptor exclusively bound testosterone with more than 98% selectivity. This high level of selectivity was achieved even when the mixture contained a large excess of female hormones.

Using x-ray crystallographic analysis, the researchers observed that the spherical cavity is distorted into an elliptical shape upon encapsulation of testosterone. They say that this conformational change contributes to the enhancement of intermolecular interactions between the receptor and the hormone.

The team also devised a way of using the receptor to detect extremely small amounts of a male hormone. They prepared a receptor-dye complex that emits bluish green fluorescence without testosterone. By adding a nanogram amount of testosterone, the fluorescence decreased considerably upon the encapsulation, representing a new ultrasensitive detection method, the researchers explained.

The post Synthetic Receptor Can Distinguish Between Male and Female Steroid Hormones appeared first on GEN – Genetic Engineering and Biotechnology News.

Source: Genengnews

Redesigned CAR-T eliminates dangerous cytokine release syndrome in lymphoma trial

Redesigned CAR-T eliminates dangerous cytokine release syndrome in lymphoma trial
Researchers led by the University of Southern California have designed a new type of CAR-T to reduce the risk of cytokine release syndrome, a side effect that can cause fever, brain swelling and other dangerous symptoms—and they have evidence from a small human study that they’re on the right track.

Source: Fierce Biotech

Top 10 Best-Selling Cancer Drugs of 2018

Top 10 Best-Selling Cancer Drugs of 2018

The first cancer drug to reach “blockbuster” status with sales of more than $1 billion was paclitaxel in 1997. Twenty years later, the median annual cost of a new cancer drug launched in 2017 exceeded $150,000, compared to $79,000 for the new cancer drugs launched in 2013, according to a report issued last year by IQVIA™ Institute for Human Data Science.

IQVIA’s report, “Global Oncology Drug Trends 2018,” showed that in the U.S., spending on cancer treatments had doubled since 2012, reaching almost $50 billion in 2017—compared with $60 billion in oncology drug costs in the rest of the world. Two thirds of the jump in U.S. cancer drug sales came from treatments launched within the previous five years, with 14 new cancer therapeutics launched in 2017 alone.

Even more sobering, IQVIA projected that U.S. cancer drug prices are expected to double again by 2022, to $100 billion, based on annual growth of 12–15%. An equivalent amount of sales is also forecast outside the U.S., where sales are expected to grow at a slightly smaller pace of between 10% and 13% annually. As a result, the global cancer drug market is projected to reach $200 billion in three years.

The challenge of containing the cost of cancer drugs was cited by panelists at “Advancing Quality Oncology Care In the Evolving Value-Based Care Landscape,” a panel discussion held April 16 in White Plains, NY, by The American Journal of Managed Care® (AJMC®) with its Institute for Value-Based Medicine®.

Manuel C. Perry, MD, director, oncology care model division leader, hematology/oncology, Crystal Run Healthcare, cited as a barrier “the amount of hoops that our practice and every other practice has to jump through that is not reimbursed, in order to get patients free drugs because $18,000 a month is impossible.

“Pharmacy benefit managers need to have better controls. Drug companies need to have better controls. We don’t want to thwart innovation, but we need to have access,” Perry said. “If the government can’t negotiate with a drug company, there needs to be some other cost-containment strategy. You can’t have no cost containment, and no [value-based] pathways, and no consequences. Something needs to happen. You have to chose one. You have to choose another. Maybe it’s a blend. I don’t know what the answer is. But what we have right now is unsustainable.”

“I think we all agree that the escalating costs are unsustainable,” added the panel’s moderator, Shalom Kalnicki, MD, chairman, department of radiation oncology, Albert Einstein College of Medicine and Montefiore Medical Center.

Top 10 Best-Selling Cancer Drugs of 2018
Top 10 Best-Selling Cancer Drugs of 2018 also available in pdf.

Below is GEN’s Top 10 A-List of top-selling prescription drugs with cancer indications. The drug that topped this list ranked third on GEN’s A-List of Top 15 Best-Selling Drugs of 2018, which included more than half of the cancer drugs that generated sufficient sales to be ranked here.

Top-selling drugs are ranked based on sales or revenue reported for 2018 by bio/pharma companies in press announcements, annual reports, investor materials, and/or conference calls. Each drug is listed by name, sponsor(s), type of drug, 2018 sales, 2017 sales, and the percentage change between both years.

The top 10-selling cancer drugs generated a combined $63.58 billion in sales in 2018, up 17.5% from $54.126 billion in 2017. Seven of this year’s top 10 showed year-over-year increases in sales, of which six enjoyed double-digit gains.

Ranking #15 through #11 among cancer best-sellers are Takeda/Johnson & Johnson’s Velcade® (bortezomib); Incyte/Novartis’ Jakafi®/Jakavi® (ruxolitinib); Genentech (Roche)’s Perjeta (pertuzumab); Merck & Co.’s Gardasil/Gardasil 9; and J&J’s Zytiga® (abiraterone acetate). The treatments generated between $2.274 billion and $3.498 billion last year.


10. Xtandi® (enzalutamide)

Astellas Pharma and Pfizer

Type of Drug: Androgen receptor inhibitor
2018 Sales: $3.624 billion (¥327.8 billion [$2.925 billion Astellas + $0.699 billion Pfizer)
2017 Sales: $3.116 billion (¥282.8 billion [$2.526 billion Astellas + $0.590 billion Pfizer)
% Change: 16.3%


9. Ibrance® (palbociclib)


Type of Drug: Kinase inhibitor
2018 Sales: $4.118 billion 1
2017 Sales: $3.126 billion 1
% Change: 31.7%


8. Neulasta/Peglasta (pegfilgrastim)

Amgen and Kyowa Hakko Kirin

Type of Drug: Leukocyte growth factor
2018 Sales: $4.684 billion ($4.475 billion Amgen + $0.209 billion [¥23.1 billion] Kyowa Hakko Kirin)
2017 Sales: $4.716 billion ($4.534 billion Amgen + $0.182 billion [¥20.1 billion] Kyowa Hakko Kirin)
% Change: -0.7%


7. Imbruvica® (ibrutinib) 

Pharmacyclics (AbbVie) and Johnson & Johnson (J&J)

Type of Drug: Kinase inhibitor
2018 Sales: $6.205 billion ($3.590 billion Pharmacyclics [AbbVie] + $2.615 billion J&J)
2017 Sales: $4.466 billion ($2.573 billion Pharmacyclics [AbbVie] + $1.893 billion J&J)
% Change: 38.9%


6. Rituxan®/MabThera (rituximab)

Genentech (Roche) and Biogen 2

Type of Drug: CD20-directed cytolytic antibody
2018 Sales: $6.750 billion [CHF 6.752 billion] 2
2017 Sales: $7.298 billion [CHF 7.300 billion] 2
% Change: -7.5%


5. Avastin


Type of Drug: Vascular endothelial growth factor–directed antibody
2018 Sales: $6.822 billion (CHF 6.849 billion)
2017 Sales: $6.662 billion (CHF 6.688 billion)
% Change: 2.4%


4. Herceptin

Roche (Genentech)

Type of Drug: HER2/neu receptor antagonist
2018 Sales: $6.951 billion (CHF 6.982 billion)
2017 Sales: $6.983 billion (CHF 7.014 billion)
% Change: -0.5%


3. Keytruda

Merck & Co.

Type of Drug: Programmed death receptor-1 (PD-1)-blocking antibody
2018 Sales: $7.171 billion
2017 Sales: $3.809 billion
% Change: 88.3%


2. Opdivo

Bristol-Myers Squibb (BMS) and Ono Pharmaceutical

Type of Drug: Programmed death receptor-1 (PD-1) blocking antibody
2018 Sales: $7.570 billion ($6.735 billion BMS + $835 million [¥92.5 billion] Ono)
2017 Sales: $5.763 billion ($4.948 billion BMS + $815 million [¥90.2 billion] Ono)
% Change: 31.4%


1. Revlimid


Type of Drug: Thalidomide analogue
2018 Sales: $9.685 billion
2017 Sales: $8.187 billion
% Change: 18.3%


1. Despite the year-over-year sales increase, Pfizer said international Ibrance revenues were negatively impacted by a one-time price adjustment to full-year 2017 revenues related to finalizing reimbursement agreements in certain developed Europe markets
2. Biogen receives a share of U.S. pre-tax profits on sales of Rituxan, which is marketed by Genentech (Roche). Sales figures do not include U.S. pre-tax profits generated by Biogen, since the company only discloses those profits combined with profits from Gazyva® (obinutuzumab), and does not break out each product separately. Biogen reported combined Rituxan-Gazyva pre-tax profits of $1.432 billion for 2018, and $1.316 billion for 2017.

The post Top 10 Best-Selling Cancer Drugs of 2018 appeared first on GEN – Genetic Engineering and Biotechnology News.

Source: Genengnews