A Peptide that Disrupts Hsp90:HIF Protein-Protein Interactions as a Therapeutic Treatment for Renal and Other Types of Cancer

Hypoxia inducible factor (HIF) is a heterodimeric transcription factor that regulates the expression of proteins involved in angiogenesis, glucose metabolism, and cell survival.  It is composed of two subunits, one of which is dynamically expressed (a) and one of which is constitutively expressed (ß) (see figure).  HIFa is stabilized in low oxygen conditions, is over-expressed in many solid tumors as a result of the hypoxic environment, and is associated with a poor prognosis.  HIFa is also a client protein for the molecular chaperone heat shock protein (HSP90).  Inventors at the Medical University of South Carolina have previously shown that pharmacologic inhibitors of Hsp90 deplete Hsp90 levels, interfere with HIF-1-mediated transcription, and antagonize angiogenesis.  It has been previously reported that HSP90 binds to the PAS-domain of HIFa.  This domain is found in several proteins and is involved in sensing and responding to changes in the cellular environment.  Conformational changes in PAS domains alter protein-protein interactions, leading to distinct signaling cascades. 

 

Disclosed here, includes the finding that Hsp90 binding in this region of HIF serves a role as a critical mediator of HIF binding partners and subsequent activity.  These inventors have developed a peptidic-based experimental approach to allow identification of the specific HSP90 binding region within this domain.  This strategy will allow our researchers to determine the dependence of HIF-1 and HIF-2 function upon Hsp90 and to understand the dynamics between HSP90 and regulatory proteins binding within the PAS domain.  Finally, this approach may lead to the development of a HIF inhibitor, which may have therapeutic potential.

New Biomarker for Diabetic Vascular Disease

Despite considerable advances in the treatment of type I diabetes, cardiovascular complications remain the primary cause of death and accounts for the greatest component of health care expenditures in people with diabetes. However, the risk factors for developing cardiovascular disease in diabetics remain undefined, until now. Researchers at the Medical University of South Carolina recently discovered a blood plasma biomarker in type I diabetes patients, that, when elevated, indicates an elevated risk of diabetic vascular disease.

A recent study was conducted based on cross-sectional data generated from the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC)-cohort of type 1 diabetic patients. An independent association was found between the biomarker levels in blood plasma of diabetics and microalbuminuria (an early indicator of renal dysfunction), hypertension, and elevated lipids. Furthermore, multivariable regression analysis provided the first evidence of an independent and positive association between the biomarker levels and surrogate markers of atherosclerosis in diabetics.

In addition, a novel single nucleotide polymorphism (SNP) in the coding region of the biomarker gene was identified. Survival analyses demonstrated that the onset of microalbuminuria occurs at a more rapid rate in diabetic subjects with the SNP than without the SNP.

Finally, the researchers discovered a novel mechanism by which the biomarker is thought to contribute to vascular inflammation/ endothelial dysfunction: The biomarker stimulates MAPK phosphorylation, independent of bradykinin signaling, and induces apoptosis of vascular smooth muscle cells. As a result, atherosclerotic plaques become instable, enhancing the risk of plaque rupture with subsequent myocardial infarction, organ failure, or stroke.

New Biomarker for Diabetic Kidney Disease

Diabetic nephropathy is the leading cause of end stage renal disease in the Western world and develops in about one-third of diabetic patients.  Although, several established risk factors such as duration of diabetes, hyperglycemia and hypertension have been shown to increase the risk to develop nephropathy, they do not solely account for the incidence and progression of diabetic nephropathy. Rather, there is growing evidence that the risk to develop diabetic nephropathy is in large part genetically determined. Although the evidence for genetic susceptibility in the pathogenesis of diabetic nephropathy is well-recognized, the causative genes remained to be identified.

Connective tissue growth factor (CTGF) is known to be an important risk factor in diabetic nephropathy.  CTGF is increased in diabetic nephropathy and correlates with the degree of albuminuria (leaking of albumin into urine, an early indicator of renal dysfunction). Researchers at the Medical University of South Carolina recently discovered a novel single nucleotide polymorphism (SNP) in the promoter region of the CTGF gene that predisposes diabetic subjects to develop albuminuria (an early indicator of kidney dysfunction). The researchers conducted a study based on cross-sectional data generated from the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC)-cohort of type 1 diabetic patients.

The novel CTGF SNP is associated with a 3-fold increased risk to develop albuminuria compared to diabetic patients without the SNP. Survival analyses demonstrated that the onset of albuminuria occurs at a more rapid rate in diabetic subjects with the polymorphism than without the polymorphism. Functional studies show that the basal activity of the mutant was significantly higher than wildtype. The novel SNP is located in one of the Smad 1 binding sites and functional analyses indicate that this region is critical for Smad1-dependent transcriptional regulation of the CTGF gene.

Novel Anabolic Osteoporosis Treatment

In osteoporosis, the net rate of bone resorption exceeds that of bone formation, resulting in frail bones. Most osteoporosis drugs currently approved by the Food and Drug Administration, focus on reducing bone resorption. Forteo® is currently the only FDA approved bone forming (anabolic) drug.  However, when it was approved in 2002, the FDA mandated that it carry a black-box warning because it was associated with an increased risk of osteosarcoma, or bone cancer, in rats. Researchers at Duke University and the Medical University of South Carolina developed a new therapeutic that could overcome some of the drawbacks of Forteo®.

Forteo® (recombinant human parathyroid hormone (PTH-1-34)) binds to the type I PTH/PTH-related peptide receptor (PTH1R). It stimulates osteoblastic activity, as well as osteoclastic activity. Intermittent treatment with PTH-1-34 by daily injection is necessary to stimulate more bone formation than bone resorption (Figure 1).

Dr. Diane Gesty-Palmer (Duke University), Dr. Louis Luttrell (Medical University of South Carolina), and Dr. Robert Lefkowitz  (Duke University) recently discovered a compound that selectively stimulates the PTH1R-mediated pathway leading to bone formation, without stimulating bone resorption.

Novel Ice Binding Proteins

Researchers at the Medical University of South Carolina and the University of Nevada have discovered a protein (produced recombinantly) shown to pit ice sheets and inhibit recrystalization (gathering of small ice crystals into larger crystals).  Semi-pure native preparations of similar proteins have shown to decrease hemolysis of red blood cells when cells were frozen, suggesting a possible protective role of these proteins in freeze-thaw injury. 

While similar proteins exist naturally, this is the first time a recombinant ice binding protein has been produced.

A Novel Therapy Promoting Myocardial Regeneration and Reducing Scarring Following Heart Attack

Coronary heart disease is the leading cause of death in the America. While one American death in every five annually is caused by coronary heart disease, treatment options remain limited.  Once injury to the heart occurs, the cardiac healing process is dominated by scar tissue formation. This leads to a diminished function of the damaged heart as a blood pump and increased risk of cardiac arrhythmia and sudden death. The exciting prospect of this licensing opportunity is that it is a potential therapy that would encourage the regeneration of heart muscle rather than scar tissue following a heart attack. A successful and safe approach to regenerative repair of the heart would truly revolutionize the standard of care for patients suffering from coronary heart disease.

This invention involves an innovative new strategy for modifying the behavior of stem cells in vivo to promote re-growth and/or repopulation of myocytes following heart attack.  As part of this novel approach, researchers at the Medical University of South Carolina have found that by blocking a key protein, scars that normally form in place of damaged myocardial tissue are reduced and, in turn, there is: (i) infiltration of new myocytes, (ii) proliferation of resident myocytes, and/or (iii) differentiation of stem cells into new myocytes (Figure).  This is the first known technology for regenerating new myocytes in vivo following a heart attack, and as such, is the only currently available treatment for enhancing and maintaining cardiac integrity, function, and viability following cardiac injury.

Novel Inhibitors of Pim-1 protein kinase to Treat Cancer

The protein kinase called Pim-1 is overexpressed in human patients with prostate cancer, as well as with other types of cancer. Its expression levels appear to predict the response to cancer therapy. Targeting Pim kinase with small molecule inhibitors has gained recent interest since it may play a critical role in cancer therapy.

Drs. Kraft and Smith at the Medical University of South Carolina have conducted high-throughput screening of a library of compounds and identified a novel pharmacophore that has Pim-1 inhibitory properties. Current efforts are focused on medicinal chemistry to optimize the structure, as well as further testing in in vitro and in vivo cancer models.

Advantages: Other groups have described Pim-1 inhibitors of a different structure but the compounds identified by Drs. Kraft and Smith are more potent.   

Novel Acid Ceramidase Modifying Compounds to Treat Cancer

Sphingolipid metabolism is recognized as a key factor in tumor cell survival and metastasis. Ceramide is a "tumor suppressor sphingolipid" involved in regulation of cell growth, differentiation, senescence and programmed cell death. Drs. Norris and Hannun, and their colleagues at the Medical University of South Carolina, have developed and tested a portfolio of novel small molecule therapeutics that target ceramide metabolism and result in cancer cell apoptosis.

The novel small molecule therapeutics were rationally designed and proven to inhibit enzymes (called acid ceramidase and sphingosine kinase) that create resistance to conventional cancer therapies. The compounds sensitize cancer cells to undergo programmed cell death, therefore they can be administered either as a stand alone treatment or in combination with "standard of care" chemotherapy or radiation therapy. Chemo-additive therapy will permit the oncologist to improve morbidity and clinical outcomes at lower, less toxic, drug or radiation doses.

Substantial preclinical data is available and the researchers continue to actively test these compounds.

A Novel Homolog of Methylphenidate as a Novel and Potent Therapeutic Agent for the Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD)

The present invention relates to a drug molecule structurally related to methylphenidate (Ritalin®, Concerta®, others) resulting from a synthetic substitution of a functional group that results in advantageous aspects for use in the treatment of child, adolescent and adult ADHD and ADHD with comorbid disorders.  Additionally, this novel molecule can likely be used for a variety of other indications including, the excessive daytime sleep associated with Narcolepsy, Obstructive Sleep Apnea/Hypopnea Syndrome, Shiftwork Sleep Disorder, depression, apathy, and a variety of other fatigue syndromes associated with diseases such as multiple sclerosis (MS) and Parkinson's Disease.  Additionally, the inherent stimulant effects of this novel compound may also be useful as a treatment to counter the problematic sedating side effects from other therapeutic agents used in treating a variety of disorders (i.e. sedating antipsychotic agents used to treat a variety of psychiatric disorders, and sedation associated with high-dose opiate analgesics)

The inventors at the Medical University of South Carolina have generated preliminary data testing relevant doses of the novel compound in animals versus control.  They have also found that unlike methylphenidate, this compound will not result in elevated blood concentrations when mixed with ethanol.  A common problem of abuse for patients prescribed methylphenidate.  See below for seven "key attributes" to this technology.

Novel Therapeutic Approach for Treating Cancer

The invention relates to a novel compound that blocks thromboxane signaling pathways in combination with standard chemotherapeutic drugs to treat invasive cancer.  The researchers have found that the use of these drugs augment the effect of chemotherapeutic drugs and sensitive cancer cells to their effect.  The addition on this novel compound has the potential to decrease nephrotoxicity associated with some chemotherapeutic agents.

This compound, and similar compounds in a similar class have been shown to suppress growth and reduce the migration and invasion of bladder cancer cells in vitro.  Several additional studies have shown, when this compound is not used, a promotion of tumor invasion and metastases.

New Therapeutic Strategies against EBV-associated Tumors and Autoimmune Disorders

Investigators at the Medical University of South Carolina have discovered a novel protein which inhibits the phagocytic process by which host macrophages ingest microbes, in particular the Cryptococcus species.  Because the novel protein prevents the binding of a key step in the complement pathway, it is hypothesized that it will likely have anti-oncogenic effects.  Additionally, the investigators hypothesize this protein could also block immune disorders characterized by overproduction of antibodies, such as autoimmune diseases (e.g. arthritis rheumatoid and lupus erythematous)

Conjugated Derivatives as Topoisomerase Poisons

Topoisomerase's serve to maintain both the transcription and replication of DNA and variations could explain differences in cancer drug sensitivity.  The researchers at the Medical University of South Carolina have found a novel class of molecules which inhibits catalytic activity of the nuclear enzyme Topoisomerase I (Topo I), which would be useful for the chemotherapy of cancer.  Additionally, the proposed compounds are chemically stable and exhibit good bioavailability properties.

Drug Delivery Vehicle to the Sinonasal Cavity

Researchers at the Medical University of South Carolina have developed a delivery vehicle to be used for nearly all sinonasal conditions, including acute/chronic rhinosinusitis, allergic rhinitis, non-allergic rhinitis, viral rhinitis, epistaxis, post-nasal drip, nasal conjestion, granulomatous/rheumatologic disorders, etc.  This vehicle could be used to deliver drugs such as steroids, antibiotics, peptide based therapeutics, mucolytics or other medications to simply to deliver saline or other hydrating/moisturizing agents. 

The advantage of this vehicle delivery system is that it remains in contact with the mucosa of the sinonasal cavity for hours without impairing mucociliary transport, as opposed to other forms of topical medication (drops, irrigations, sprays, etc) that contact the mucosa and then are rapidly swallowed down the throat.  Other delivery vehicles such as gels are too viscous and impair mucociliary clearance, leading to stasis of secretions and infections.  This delivery vehicle overcomes both of these problems

A Compound to Accelerate Bone Fracture Healing and Regeneration

Researchers at the Medical University of South Carolina have discovered a novel protein with bone regenerative properties.  Following traumatic bone breaks such as auto accidents, falls from height, or military battles, bones take a prolonged period of time to heal, with some breaks not healing at all.  The proposed invention is a novel therapeutic protein which will stimulate bone regeneration quicker and more efficiently than current therapies, resulting in less healing time for the patient. 

Metabolically Stable Puromycin Analogs to Treat Cancer

Provided are potentially novel puromycin analogs with antitumor activity, wherein the formation of toxic metabolites is blocked.

Puromycin is a long-known antibacterial/antitumor agent. It inhibits protein synthesis by acting as a mimic of aminoacyl-tRNA.  The amino acid is incorporated in the growing protein, but cannot be hydrolyzed from the nucleoside moiety because of the amide bond. Therefore, puromycin acts as a substrate and a terminator.

The major drawback of administering puromycin is the metabolic conversion to puromycin amino nucleoside (PAN), which is further converted to a nephrotoxic metabolite. This nephrotoxicity has limited the clinical use of puromycin as an anticancer agent. To solve this problem, Dr. Guiseppe Gumina and his colleagues at the Medical University of South Carolina synthesized a series of stable puromycin analogs that mimic puromycin activity, but are incapable to undergo metabolism to PAN. In preliminary studies, the target compound showed cytotoxicity comparable to that of puromycin in breast cancer and leukemia cell lines.

The newly synthesized analogs may provide promising chemotherapeutic agents with the effectiveness of puromycin, but without nephrotoxicity.   

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