Scripps Research Institute Scientists Find a Potential Cause of Parkinson’s Disease that Points to a New Therapeutic Strategy

 For a high-resolution image see: http://www.scripps.edu/news/press/
images/reed_steve/reed_steve.jpg
LA JOLLA, CA – July 24, 2013 – Biologists at The Scripps Research Institute (TSRI) have made a significant discovery that could lead to a new therapeutic strategy for Parkinson’s disease.
The findings, recently published online ahead of print in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson’s disease. Precisely how the loss of this enzyme leads to the deaths of neurons has been unclear. But the TSRI researchers showed that parkin’s loss sharply reduces the level of another protein that normally helps protect neurons from stress.
 http://www.scripps.edu/news/press/2013/20130724reed.html

Isis Phase II drug APOIIIRx slashes triglycerides by 64%

Isis Pharmaceuticals is "very encouraged" by a second set of mid-stage data for its heart drugAPOIIIRx, which shows that it can substantially slash levels of dangerous fats in the blood. 

In a 26-patient Phase II trial, patients with severely high levels of triglycerides taking Isis' drug alongside fibrates experienced 64% drop in triglycerides, and a 70% drop in apolipoprotein C-III (apoC-III), a component of 'bad' low-density lipoprotein
read all at
.http://www.pharmatimes.com/Article/13-07-23/Isis_PhII_drug_slashes_triglycerides_by_64.aspx

New therapy for pancreatic cancer: Phase III clinical trial currently recruiting Australian patients

Currently there is a clinical trial that is recruiting patients from around the globe including sites across Australia. The trial is testing MM-398; a therapy that uses the latest in nanotechnology to deliver the chemotherapeutic agent irinotecan encased in a liposome to cancer patients.¹ In particular this trial, named NAPOLI-1 (NAnoliPOsomaL Irinotecan) is recruiting patients with pancreatic cancer who have previously been treated with the chemotherapy agent gemcitabine unsuccessfully i.e. their disease has gone on to spread/progress despite this treatment.<sup>2,3
read all here

http://www.virtualmedicalcentre.com/news/new-therapy-for-pancreatic-cancer-phase-iii-clinical-trial-currently-recruiting-australian-patients/18708</sup>


irinotecan

Irinotecan (Camptosar, Pfizer; Campto, Yakult Honsha) is a drug used for the treatment of cancer.

Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin.

Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI, which consists of infusional 5-fluorouracil,leucovorin, and irinotecan.

Irinotecan received accelerated approval by the U.S. Food and Drug Administration (FDA) in 1996 and full approval in 1998. During development, it was known as CPT-11.

Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.

Merrimack currently has six oncology therapeutics in clinical development, multiple product candidates in preclinical development and an active Systems Biology-driven discovery effort. 
MM-398
(Nanotherapeutic)

• Indication:
• Description:
• Target

• Pancreatic Cancer (2^nd line, 2 indications), Colorectal Cancer, Glioma
• Nanotherapeutic
• Encapsulated irinotecan

MM-398 is a nanotherapeutic consisting of the chemotherapuetic irinotecan, encapsulated in a liposomal sphere. MM-398 is designed to rely on the natural blood flow of the tumor to direct the therapy directly to the site of the cancer and minimize exposure to non-target cells.

MM-398 in the Clinic

MM-398 is being evaluated in clinical trials for its ability to treat tumors resistant to chemotherapy across multiple types of cancers, including pancreatic, lung, colorectal and glioma. The FDA and the European Medicines Agency granted MM-398 orphan drug designation in 2011 for the treatment of patients with metastatic pancreatic cancer who have previously failed treatment with the chemotherapy drug gemcitabine. Our Phase 3 study, NAPOLI-1 (NAnoliPOsomaL Irinotecan), is currently underway.
posters
http://merrimackpharma.com/library/research/mm-398-preclinical-posters

Phase III prostate cancer trial for 'homing' injection shows improvements

Phase III prostate cancer trial for 'homing' injection shows improvements
A new treatment for advanced prostate cancer that homes-in on tumours to deliver a high-energy burst of radiation to cancer cells has shown significant benefits in a large scale clinical trial.
The trial of 921 patients showed that treatment with the radioactive Radium-223 gave men with late-stage prostate cancer an average extra of 15 weeks of life.http://www.pharmaceutical-technology.com/news/newsphase-iii-prostate-cancer-trial-for-homing-injection-shows-benefit?WT.mc_id=DN_News

Blood cancers – perifosine

An important target in cancer treatment is the serine/threonine specific protein kinase Akt, or protein kinase B. This kinase is involved in the pathway that prevents cell death, inhibiting apoptosis, and therefore inhibiting Akt may lead to cancer cell death.

One such compound is perifosine, discovered by Aeterna Zentaris and being developed by Keryx Biopharmaceuticals.1 Numerous clinical trials have been carried out in solid tumours, with varying success, and it failed a Phase III trial in colorectal cancer in 2012. However, it continues in trials for blood cancers such as lymphomas, where it shows promise.

In one Phase I/II trial, it was evaluated in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma who had previously received bortezomib therapy.2 A total of 84 patients, three-quarters of whom were refractory to bortezomib, and half to both bortezomib and dexamethasone, were given 50mg/day of perifosine, plus 1.3mg/m2 bortezomib, and 20mg dexamethasone added if progression occurred. The overall response rate was 43% in the 73 evaluable patients – 65% in the bortezomib-relapsed group and 32% in bortezomib-refractory patients. It was generally well tolerated, with manageable gastrointestinal events and fatigue. The median progression-free survival was 6.4 months, and a median overall survival of 25 months – 22.5 months in those refractory to bortezomib.

Perifosine

- See more at: http://www.manufacturingchemist.com/technical/article_page/Blood_cancers__perifosine/88596

http://www.manufacturingchemist.com/technical/article_page/Blood_cancers__perifosine/88596#sthash.2bv5XjRe.dpuf

Anticancer agent – elacytarabin

Elacytarabine

Cytarabine is a cytosine derivative that is a common component of chemotherapy regimens for blood cancers such as acute myeloid leukaemia (AML), and because it can cross the blood–brain barrier, it is useful in the treatment of central nervous system lymphomas. However, the response is variable, and resistance commonly develops via multiple mechanisms. Its activity is dependent on the intracellular concentrations of the active phosphorylated form, and one of the main mechanisms of resistance involves the deficiency of the transporter molecule hENT1 that carries it into the cells. As a result, Clavis Pharma developed a lipophilic ester derivative, elacytarabine, whose cellular uptake is not hENT1-dependent.1

- See more at:http://www.manufacturingchemist.com/technical/article_page/Anticancer_agent__elacytarabine/83035

 http://www.manufacturingchemist.com/technical/article_page/Anticancer_agent__elacytarabine/83035#sthash.bF8Vqa3M.dpuf

Fadrozole (marketed as Afema by Novartis) for the treatment of breast cancer.

 

Fadrozole (INN, marketed as Afema by Novartis) is an aromatase inhibitor^[1] that has been introduced in Japan for the treatment of breast cancer.

It is selective.^[2]

1. Raats JI, Falkson G, Falkson HC (January 1992). "A study of fadrozole, a new aromatase inhibitor, in postmenopausal women with advanced metastatic breast cancer". J. Clin. Oncol. 10 (1): 111–6. PMID 1530798.
2. Browne LJ, Gude C, Rodriguez H, Steele RE, Bhatnager A (February 1991). "Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease". J. Med. Chem. 34 (2): 725–36.doi:10.1021/jm00106a038. PMID 1825337.

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer and ovarian cancer inpostmenopausal women. AIs may also be used off-label to treat or prevent gynaecomastia in men.

Aromatase is the enzyme that synthesizes estrogen. As breast and ovarian cancers require estrogen to grow, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors.

Types of AIs

There are 2 types of aromatase inhibitors (AIs) approved to treat breast cancer:

• Irreversible steroidal inhibitors, such as exemestane (Aromasin), forms a permanent and deactivating bond with the aromatase enzyme.

• Non-steroidal inhibitors, such as anastrozole (Arimidex), inhibit the synthesis of estrogen via reversible competition for the aromatase enzyme.

Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue. The main source of estrogen is the ovaries inpremenopausal women, while in post-menopausal women most of the body's estrogen is produced in peripheral tissues (outside the CNS), and also a few CNS sites in various regions within the brain. Estrogen is produced and acts locally in these tissues, but any circulating estrogen, which exerts systemic estrogenic effects in men and women, is the result of estrogen escaping local metabolism and spreading to the circulatory system.