Systemic Indications

 

Systemic IndicationsKennedy’s Disease - Spinal and Bulbar Muscular Atrophy

KENNEDY’S disease (spinal and bulbar muscular atrophy) is a rare X-linked inherited form of motor neuron disease with onset in males due to a mutation in the first exon of the androgen receptor (AR) gene. The syndrome is characterized by progressive muscle weakness and atrophy whose onset is usually in the fourth or fifth decade, but may be as early as the midteens and as late as 60 yr. Currently there are no therapies available and limited treatments in development for Kennedy’s disease patients.

Key animal model studies have indicated that ARD enhancers limit the progression and severity of Kennedy’s disease symptoms using SBMA mice (transgenic mice carry human Kennedy’s disease AR gene) models. AndroScience will aggressively pursue options to accelerate remaining preclinical validation studies on the ARD enhancer’s potential to impact Kennedy’s disease progression and in 2009 actively begun to seek resources to move the program into the first clinical stage of development.

 

Prostate Cancer

Complete androgen blockade (CAB) therapy, where patients receive chemical or surgical castration and conventional anti-androgen treatment, has been used to enhance survival in patients with metastatic prostate cancer. These drugs prevent the production or block the action of testosterone and other male hormones. Two classes of drugs are used; one to reduce androgen synthesis and the other to prevent androgens from binding to the AR. The most commonly used drugs as hormonal therapy in prostate cancer include the LHRH analog(s) (luteinizing hormone-releasing hormone analogs) or medical castration — class of drugs which prevent testosterone production by the testes; and the non-steroidal androgen receptor antagonists — class of drugs which compete the binding of androgen to AR and thus block the action of testosterone at the prostate.

Numerous in vitro and in vivo prostate cancer models indicate ARD enhancers lower prostate cancer tumor markers including PSA, reduce tumor volume, and significantly outperform common first line treatments such as the anti-androgens and DHT converting enzyme inhibitors. These tumor inhibiting effects of ARD enhancers are seen both in the presence and absence of DHT.

Potential advantages of using an ARD Enhancer (such as ASC-J9®), to treat Prostate
Cancer:

  1. ARD enhancer inhibits tumor cell growth in vitro and in vivo regardless whether androgens are present or not. Therefore, patients receive ARD enhancer treatment may not require the pretreatment castration (chemical or surgical).
  2. Since ARD enhancer is not competing with endogenous androgens binding to AR, to sustain a high concentration and longer time of drug in circulation may not be necessary.
  3. Unlike some conventional anti-androgen ARD enhancer possesses no “agonistic (or androgenic)” activity, thus may prevent tumor from become “hormone-refractory”, and can be uses to treat refractory tumor.
  4. Since ARD enhancer induces degradation of AR, this would avoid all other non-ligand factors that could activate AR and tumor growth via different activation pathways;
  5. ARD enhancer could be used specifically for the relapse tumors that over express AR.

 

Benign Prostatic Hyperplasia (BPH)

Systemic IndicationsBenign adenomatous hypertrophy of the periurethral prostate gland, benign prostatic hyperplasia (BPH), causes variable degrees of bladder outlet obstruction. In addition to surgical treatment of BPH, current pharmacological management involves the use of alpha-blockers to facilitate urination by relaxing muscles where the bladder transitions to the urethra, anticholinergics to increase the bladder's functional capacity, inhibit involuntary contractions and slightly inhibit the urge to urinate frequently; or the use of 5-alpha reductase inhibitors, such as dutasteride and finasteride, to shrink the prostate gland. However, these inhibitors may only cause slight improvements for men encountering significantly enlarged prostates and often take considerable time for symptomatic relief to occur.

Given the central role androgens play in BPH and the utility of conventional anti-androgens in treating the progression of symptoms, ARD enhancers have a capacity to significantly impart reductions in the growth of the prostate and even cause it to become smaller, which will directly alleviate symptoms of BPH. Furthermore the mechanism of action and unique ability for ARD enhancers to reduce AR levels in the prostate may result in a more lasting reversal of prostate enlargement.

 

AR Related Solid Tumors: Hepatocellular Carcinoma and Bladder Cancer

The androgen receptor has recently emerged as a potential therapeutic target for the treatment of hepatocellular carcinoma (HCC) and bladder cancer. Studies have suggested that androgens might contribute to the gender difference of HCC incidence and that serum testosterone may be positively linked to the development of HCC. Based on epidemiologic, experimental observations, and notably the fact that men have a substantially higher risk of bladder cancer than women, androgens and/or the AR is also hypothesized to play a role in bladder cancer initiation.

In evaluating the AR as a therapeutic target for treatment of HCC, ASC-J9® has been shown to suppress HCC progression. Analysis of harvested bladder cancer tumors has also demonstrated that ASC-J9® decreased the proliferation index, increased the apoptotic index, and reduced levels of angiogenic factors and other metastasis-related factors.  Taken together, AR degradation enhancers offer new perspective on treating important solid tumors not historically known to respond to androgen mediated effects.

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