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Attacking Brain Cancer in its Hypoxic Environment

As tumors grow and become unresponsive to external cellular signals, the level of oxygen in the masses decreases; mutated cells, those with malfunctioning p53, grow and thrive greater than 0.2 mm from the blood supply.

Radiation therapy works by killing capillaries of newly forming blood vessels and by generating high energy free radicals that damage DNA and kill cells. For radiation to be effective, oxygenation is needed.

Hypoxic cancer cells are 2-3 more time resistant to radiation therapy than cancer cells growing in conditions of normoxia. Furthermore, hypoxic cancer cells decrease their metabolic rate, which further imparts resistance to treatment by radiation and chemotherapy. Hypoxic conditions also trigger angiogenesis, a critical step in cancer progression

TSC (trans sodium crocetinate) is a molecule that when injected in the blood stream, increases the oxygenation of tumors, even those in the central nervous system.

TSC molecule

During Diffusion Pharmaceutical’s preclinical studies in rats, glioblastoma cells were surgically implanted in the brains and the rats were then divided into three groups.  In the control group (group of rats which did NOT receive any treatment) all the rats died within 29 days. In the second group, which received radiation therapy at 10 days post tumor implantation but not TSC, 28% were alive at 60 days.  In the third treatment group, which received an IV injection of TSC prior to radiation therapy, survival increased to 73%.

Hypoxia

Sheehan J, et al. Trans sodium crocetinate sensitizes glioblastoma multiforme tumors to radiation. J Neurosurg 108:972-978, 2008.  See also, Sheehan J, et al, TSC with Radiation and Temozolomide; J Neurosurg 113:234-239, 2010

At 60 days, complete tumor remission was seen in the survivors of the “radiation therapy plus TSC” group, whereas tumor regrowth was observed in survivors in the “radiation therapy alone” group.

On September 4, 2014, the company raised $3.5 MM to advance the compound, which is undergoing Phase II trials at 18 major cancer centers around the country. The compound, which is being tested in conjunction with radiation therapy, has been granted orphan drug designation for newly diagnosed primary brain cancer, or glioblastomas, as well as brain metastasis.

 

 

 

cancerBiology180x110

Obesity soon to replace tobacco as the number one preventable / treatable cause of cancer

“Obesity is on its way to replacing tobacco as the number one preventable / modifiable cause of cancer,” says Clifford Hudis, MD, the 2013-2014 President of the American Society of Clinical Oncology. Indeed, obese post-menopausal women have up to twice the risk of developing breast cancer as do their normal weight counterparts.

First, the biology behind the link to between obesity and cancer:

  1. Obese patients have increased levels of insulin and IGF-1 (insulin-like growth factor 1), therefore, greater stimulation IGF-1R (insulin-like growth factor receptors), which drive cell growth and cell division;
  2. Adipocytes have direct and indirect effects on cellular signaling molecules (stimulation of mTOR – mammalian target of rapamycin, which is one of the terminal Akt/PKB pathway effectors resulting in myc induction, and inhibition of AMP-activated protein kinase which blocks mTOR induction of myc);
  3. Obesity induces a chronic subacute level of inflammation, which promotes the development of cancer.

igf-1r-mechanism

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Second, what is the definition of obesity? The BMI (body mass index) chart from Baylor (http://www.baylorhearthospital.com/Knowing-Your-Numbers.html) shows the BMI given your height and weight. If you are 5’6” and weigh 230 pounds, or 6’2” and weigh 270 pounds, you are severely obese.

bmi_chart

Third, some more startling facts:

  1. In colorectal cancer, obesity at the time of diagnosis is linked to a higher risk of recurrence and death;
  2. Obese and overweight women have 2-4 times the risk of developing endometrial cancer, and 90% of women with the most common type of endometrial cancer (Type 1) are obese;
  3.  Individuals with a BMI of 30 or more, have 2 times the risk of developing pancreatic cancer;
  4. 30% of new cases of kidney cancer are attributable to obesity;
  5. BMI is positively correlated with prostate cancer progression to lethal disease, while inversely associated with incidence.

And finally, the obesity epidemic is only getting worse, especially in children where the rate of childhood obesity in 6 to 11 year olds increased from 5% in 1980 to 18% in 2010, and for 12 to 18 year olds it increased from 7% in 1980 to 18% in 2010.

Obesity of preventable and treatable. We must do a better job.

Here’s the link…tell me what you think

cancerBiology180x110

Why more males develop brain tumors than females

It is widely known that brain tumors, in particular glioblastomas and medulloblastomas, affect males more than females. Moreover, given the age of onset and analysis of incidence by age, sex hormones have been ruled-out as the cause. Continue reading

cancerBiology180x110

Kyprolis FOCUS Phase 3 Study for Multiple Myeloma

Last week, Amgen (Onyx) announced negative news from its FOCUS clinical trial of multiple myeloma drug Kyprolis. Let’s put this into perspective. Continue reading

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JAK-inhibitors for myelofibrosis

Last week, pacritinib, an oral tyrosine kinase inhibitor drug-candidate with dual activity against JAK2 and FLT, has been granted Fast Track designation by the U.S. Food & Drug Administration Continue reading

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IDO inhibition in cancer immunology

IDO ( indoleamine 2,3-dioxygenase) is a molecule that oxidizes tryptophan, which is needed by cytotoxic T-cells. When cancer cells and T-reg cells secrete IDO in the vicinity of cytotoxic T cells, antitumor activity is abrogated.   Continue reading

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Targeted therapies for cancer – overview

The National Cancer Institute has a very informative, yet easy to understand overview  presented as a Q&A – Targeted Cancer Therapies. Continue reading

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Monoclonal antibodies + kinase inhibitors are better than antibodies alone in breast cancer and B-cell lymphoma

The combination of Herceptin plus pan-HER (EGFR and Her 2 an 4) kinase inhibitor neratinib resulted in a 33% improvement in progression free survival versus Herceptin alone in breast cancer patients.  Rituxan combined with idelalisib, PI3K inhibitor, resulted in a near doubling of progression-free survival at 24 weeks versus Rituxan, alone in patients with Chronic Lymphocytic Leukemia, non-Hodgkin’s Lymphoma, and small cell lymphoma.  The news for neratinib tripled the valuation of Puma Biotechnology, while the FDA granted approval of Gilead’s drug Zydelig (idelalisib). Continue reading

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Cancer diagnostics in clinical use

Diagnostics that not only diagnose cancer, but also help select the appropriate therapy and monitor response are a mainstay in modern oncology, and their use is growing.  Precision medicine, identifying genetic markers of disease and designing treatments to exploit these, is the essence of  targeted cancer therapy.   Continue reading

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Genspera G-202 – anti-cancer hand grenade

Genspera is a company developing novel prodrugs for the treatment of cancer.  In a phase 2 study in patients with hepatocellular carcinoma who have failed treatment with Nexavar (sorafenib), a tyrosine kinase inhibitor that blocks KIT, FLT-3 RET, raf, VEGFR1-3, and PDGF kinases, a doubling of time to progression was seen in patients taking G-202. Continue reading