Most of us think of the heart as a highly sophisticated and durable pump. But another function of the heart is to secrete peptide hormones, which are small proteins that function as hormones. Multiple hormones are encoded by the atrial natriuretic factor (ANF) gene that help to regulate blood pressure and volume. At the Experimental Biology 2008 conference in San Diego this April, Dr. David Vesely, a doctor at the James A. Haley Veterans Hospital in Tampa and a professor at the University of South Florida (USF), will present findings that hormones from the heart are also extremely effective at fighting both pancreatic and breast cancers in mice, with no observed side effects. More than 75% of mice treated with the hormones were cured of human pancreatic cancer, and more than 66% of mice with human breast cancer were cured, according to Dr. Vesely. No other treatments were given. In uncured mice with pancreatic cancer, which is fast-moving and typically has a poor prognosis, tumors still shrank to less than 10% of their original size.

The hormone treatments have not yet been tried with humans, and a private biotechnology company is now raising money to start trials. We can only hope that the treatment will work equally well in humans, but the sobering fact is that a mouse with cancer is in a lot better luck than a human, since many treatments that work in mice do not translate to humans. 

Source: EurekAlert!

The main function of DNA is to encode the building blocks of proteins, and molecular biologists have become quite adept at cutting and pasting stretches of DNA to make nearly any protein they can envision. Unfortunately, small molecules, which are some of the most effective drugs, cannot usually be built so readily. Rather, synthetic organic chemists must use a bag of tricks and years of experience to synthesize compounds that on paper sometimes appear rather simple. However, several companies are taking advantage of a modular approach, programmed using DNA, for building diverse libraries of polyketides, naturally occurring small molecules with huge pharmaceutical promise. Two such companies include Biotica and Kosan Biosciences, which made Biotech Mashup’s list of the 15 companies with the potential to change medicine.

Polyketides, which are produced by diverse microorganisms found in places ranging from the soil to the oceans, are a structurally diverse family of natural products with an extremely broad range of biological activities and pharmacological properties. Numerous drugs spanning many therapeutic areas, such as antibiotics (e.g.erythromycin A), anti-cancer compounds and antifungals, have been derived from approximately 10,000 known polyketides. According to Biotica, polyketide natural products account for medicinal sales in excess of $20 billion per year.

The combinatorial potential of polyketide synthesis is what attracts the attention of scientists and pharmaceutical companies. Polyketide synthesis is performed by large modular multisubunit enzymes known as polyketide synthases (PKSs). The addition of each individual building block to a growing polyketide chain can be performed by a separate module of the PKS. These PKS mega-enzymes are composed of gene modules encoding the active sites for the successive activation, modification and elongation of carbon building blocks. By mixing and matching catalytic components, it is thus possible to genetically specify polyketide compounds using DNA and molecular biology. As described by Biotica, PKSs can be viewed as molecular assembly lines, in which every element of functionality of the polyketide product can be identified with a specific enzyme workstation.  It is estimated that a polyketide synthesis system with just 6 modules can theoretically produce over 100,000 compounds. Large polyketide libraries can be generated by assembling a gene with various combinations of altered DNA fragments. Novel compounds can also be produced using synthesized “starter units” that are fed to engineered microorganisms to be used as precursors.

Kosan is currently focusing on anti-cancer compounds, and has numerous drugs in its pipeline spanning the preclinical to Phase 2 development phases. Compounds currently in Phase 2 development target breast cancer, melanoma, and multiple myeloma. Biotica also has a portfolio of anti-cancer compounds, and is partnering with Wyeth on its mTOR inhibitor anti-cancer drugs. Importantly, both Biotica and Kosan are targeting Hsp90 (heat shock protein 90), a protein that interacts with several sets of signaling proteins and whose disruption leads to degradation of the interacting proteins that can promote cancer.

The ability to “program” small molecule synthesis in a combinatorial fashion is truly exciting. Given the proven utility of polyketides as drugs, we have good reason to believe there will be some great drugs coming from Biotica and Kosan.

If I told you in the future you will be able breath into a device and know if you have cancer, would you believe me or would you ask me what new science fiction book I was talking about? Menssana Research would tell you that the future is now. They have developed and tested a new device that requires you to only breathe and then it can determine if you have cancer or other common ailments such as Tuberculosis. If successful in this endeavor, this will be a revolution in diagnostic testing and is the reason that Menssana Research has made Biotech Mashup’s top 15 picks for companies that have the potential to change medicine.

Diagnostic test using your breath is not a new idea. Spirometry, pulmonary lung function testing, is believed to date back as early as sometime between 129-200 A.D. when Galen did volumetric testing on a boy. In 1852, John Hutchinson, developed a water spirometer which is still in use today. Spirometry testing can be used to help determine a number of ailments such as, chronic bronchitis, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, and emphysema. Similar to volumetric testing but distinct in that biomarkers can be used for disease determination is the analysis of volatile compounds in breath. Many credit the technology basis of volatile diagnostic testing to Linus Pauling, who in 1971 found that normal breath contains volatile organic compounds. However, some argue that this credit should be given to Robert Borkenstein, who in 1954, developed the breathalyzer to measure the amount of blood alcohol in an individual. Regardless of who is to be given credit little else has advanced this form of diagnostic testing for the last 35 years.

Menssana Research Incorporated, founded by Doctor Michael Phillips, believes it is time for a leap forward. The Breathscanner is the first clinical device offered by Menssana. The concept behind the Breathscanner seems simple; collect a person’s breath and analyze the unique volatile organic compounds, VOCs, which can be indicative of disease. The reality though is different as the typical concentration of VOCs in a breath is very low and nobody knows what VOC profiles indicate disease. To address these problems Menssana put to use two analytical techniques known to have very good sensitivity, gas chromatography and mass spectroscopy. Using these instruments to analyze the VOCs in someone’s breath they have been able to put together what they have coined “breath methylated alkane contour, BMAC.” A person’s BMAC is a unique profile which can be used to determine someone’s risk for numerous diseases such as, heart transplant rejection, lung cancer, breast cancer, pulmonary tuberculosis, and other diseases. The Breathscanner was recently shown at DARPA Tech 2007, and was a big hit.

In 2004, the FDA gave Humanitarian Device Exemption status to Menssana for a heart transplant rejection breath test. Even though HUD is intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year, this was a huge step for Menssana. Moving forward Menssana is well funded and pushing for commercialization of numerous new diagnostic tests. Speaking via email with Dr. Michael Phillips he was kind enough to respond to our request for information letting us know, “The next big things in breath testing will be:

The Lungscreen breath test for lung cancer: This has been validated in three published multicenter studies(…)It has a CE Mark that approves it for marketing in Europe. NIH has awarded us a $3M grant to perform a multicenter validation study in the USA in order to obtain FDA approval.

Breath test for breast cancer:  NIH funded us to perform a pilot study that demonstrated breath biomarkers of breast cancer (publications on our website). We are now evaluating a point-of-care breath test for breast cancer that will deliver results in minutes. No radiation, no breast compression, no pain – it is completely safe.

Breath test for pulmonary tuberculosis: NIH funded us to perform a pilot study that demonstrated breath biomarkers of pulmonary TB. We are currently analyzing the data from a large multicenter international validation study. Results soon, we hope.”

Biotech Mashup is very impressed with the work done by Menssana Research and how far they have come in developing this technology. However, we recognize that with the use of mass spectrometry and gas chromatography equipment for analysis, these types of test will still be required to be sent to a diagnostic laboratory thus taking days for the patient to know the test results. The diagnostics field is having a big push for results to be available in the office while you visit your doctor. We know Menssana may be addressing this as they are currently in development of a next generation system. We are eager for the day that we can walk into our doctor’s office and do a quick breath test to let us know if we are healthy or if we need immediate treatment.

MicroRNA’s are short single stranded ribose nucleic acids which regulate gene expression. They have been found in heart and muscle tissue, and some exclusively in the brain. The term was first introduced in 2001 in Science. Researchers at Rockefeller University have discovered that microRNA’s also help create our skin to protect us from bacteria and possible prevent skin cancer.

The lead authors, Yi and Fuchs, used mouse models to find where the microRNA was expressed. During the first 13th days of development, mouse skin is primarily composed of undifferentiated stem cells. On the 15th day, these stem cells exit the inner layer of the skin and begin to differentiate into cells that form the outermost, protective layer. During this time the expression of microRNA-203 skyrockets, suggesting that during development microRNA-203 has some responsibility in creating the skin barrier. When they compared this expression to humans, chickens, and zebrafish they found the pattern was identical. Yi was quoted saying “If it has been expressed in this very specific tissue for a long time and across several species, it means that it probably plays an important role there.” This group further found that the microRNA-203 suppresses a protein, p63, which stimulates skin cell growth. Without the presence of the RNA the skin grows uncontrolled, a possible reason for some skin cancers.

This is a great find to further introduce new targets for cancer drugs. In this case the authors suggest recovering microRNA-203 expression if it fails to prevent these type of cancers. In mice models this would be great evidence that certain squamous cell carcinomas are due to the lack of microRNA-203, however this could be extremely difficult to do in humans. Another possible cheaper alternative would be to design an inhibitor to the protein, p63.

Investigators at Saint Jude Children’s Research Hospital have announced new research which has advanced the understanding of how cells undergo Apoptosis. Apoptosis is intentional programmed cell death and is believed to be one of the main reasons for the existence of cancer which hijacks apoptosis and prevents it from occurring. A report on this work can be found in the advanced online publication in Nature.

James Ihle, Ph.D., and senior author describes the work, “This is probably the first description of what is happening mechanistically that contributes to the ability of cells to delay apoptosis,(…)it provides incredible insights into how three proteins work and how they can control apoptosis.” The researchers demonstrated in mouse lymphocytes that a protein, Hax1, is required to suppress apoptosis. Briefly, Hax1 interacts with the protease Parl which allows HtrA2 to be presented to Parl. Ultimately the presence of HtrA2 prevents Bax to become activated, and Bax is known as one way to initiate apoptosis.

This detailed look at the mechanisms behind apoptosis are extremely beneficial to further preventing cancer. Similar to pharmaceutical companies targeting Angiogenesis, Apoptosis drugs is believed to be another way to slow down or even prevent many forms of cancer. By figuring out ways to initiate apoptosis in cancer you effectively rid cancer, remember cancer is define as uncontrolled cell growth due to the lack of cells undergoing apoptosis. With this type of research the drug industry will be screening and targeting proteins found in this paper and hopefully have similar success stories such as Avastin from Genetech.