SOME LITTLE GENES WITH A BIG IDEA: SHP GENE

IF YOU KNOW HOW IMPORTANT ESTROGEN RECEPTORS ARE IN BREAST CANCERS,
IF YOU KNOW HOW IMPORTANT ANDROGEN RECEPTORS ARE IN PROSTATE CANCER
IF YOU REALIZE HOW IMPORTANT THE THYROID FUNCTION IS DRIVING THE RATE OF METABOLISM
IF YOU REALIZE THE DIFFICULTY THAT POSES HEPATOMA IN TERMS OF TREATMENT,
IF YOU KNOW THAT SARCOMA IS TOUGH TO TREAT,

THEN YOU SHOULD DIG DEEPER IN UNDERSTANDING THAT ALL THESE RECEPTORS HAVE ONLY ONE INHIBITOR, THE "SMALL HETERODIMER PARTNER"  GENE!

WHAT IS IT AND HOW AND WHEN SHOULD IT COME IN?

Small heterodimer partner has been shown to interact with:

• Androgen receptor,^[4]
• Estrogen receptor alpha,^[5]
• Hepatocyte nuclear factor 4 alpha,^[6]
• Liver receptor homolog-1,^[7][8]
• Liver X receptor alpha,^[7]
• Peroxisome proliferator-activated receptor gamma,^[9]
• Retinoic acid receptor alpha,^[10][11] and
• Retinoid X receptor alpha.^[6][7]

I refuse to comment on the PPARgamma for now, did you know that this is the staff that interacts with Rb1?  watch it as it is coming to a Diabetic control and evaluation near you!

At CRBCM we are working hard!

A few notes on Prostate Cancer Prevention

Prostate cancer prevention by Finasteride and Dutasteride
Yes, these 5 alpha-Reductase Inhibitors did reduce Prostate cancer occurrence,
but in those where it did occur, it seems to be high grade when exposed to these drugs.
That is why the advisory Committee felt that these were not the best as a prevention intervention!

Vitamin E, on the other end, at 400 IU (a high dose), increased the risk of prostate cancer!

When it comes to Saw Palmetto, Wikipedia adds:

"It is also an expectorant, and controls irritation of mucous tissues. It has proved useful in irritative cough, chronic bronchial coughs, whooping-cough, laryngitis, acute and chronic, acute catarrh, asthma, tubercular laryngitis, and in the cough of phthisis pulmonalis. Upon the digestive organs it acts kindly, improving the appetite, digestion, and assimilation. However, its most pronounced effects appear to be those exerted upon the urino-genital tracts of both male and female, and upon all the organs concerned in reproduction. It is said to enlarge wasted organs, as the breasts, ovaries, and testicles, while the paradoxical claim is also made that it reduces hypertrophy of the prostate. Possibly this may be explained by claiming that it tends toward the production of a normal condition, reducing parts when unhealthily enlarged, and increasing them when atrophied.^[4]

Saw palmetto extract is the most popular herbal treatment for benign prostatic hyperplasia,^[5] a common condition in older men. Early research indicated that the extract is well-tolerated and suggested "mild to moderate improvement in urinary symptoms and flow measures."^[5][6] Later trials of higher methodological quality indicated no difference from placebo.^[7][8] Questions of adequate blinding and delivery of any active ingredients remain.^[9] The latest Cochrane Database review (2009) concludes that "Serenoa repens was not more effective than placebo for treatment of urinary symptoms consistent with BPH."^[1]
A 2001 study published in JAMA (The Journal of the American Medical Association) reported on a double-blind study study that eleven North American clinics conducted on 369 men. The study found that saw palmetto fruit extract failed to reduce urinary tract symptoms more than placebo.^[10] Men in the experimental group experienced a 2.20 point drop in their American Urological Assn. Symptom Index (AUASI) score. However, men in the placebo group saw a 2.99 point drop. The Los Angeles Times reports, “42.6% of the men in the extract group saw their AUASI scores fall by at least three points; 44.2% of the men in the placebo group saw the same degree of benefit.” The study was funded by several offices within the NIH, including the National Center for Complementary and Alternative Medicine.”^[11]
Inhibition of both forms of 5-alpha-reductase with no reduction in cellular capacity to secrete prostate-specific antigen is indicated.^{[12][13][14][15]} Other proposals for mechanisms of action include interfering with dihydrotestosterone binding to the androgen receptor, relaxing smooth muscle tissue similarly to alpha antagonist drugs, and acting as a phytoestrogen.^[16][17]
Limited in vitro and animal model studies suggest possible anti-tumor activity and potential for use in the treatment of cancer.^[12][18][19] These results have not been substantiated with human trials.
Saw palmetto extract has been suggested as a potential treatment for male pattern baldness.^{[20]" wikipedia}

In a retrospective review of Lung cancers , use of Beta blockers may provide survival advantage

*In a retrospective review of Lung cancers , use of Beta blockers may provide survival advantage.

*Ruloxitinib, still the success story in JAK driven diseases.  For JAK driven disease to be seen more in Hematologic malignancy, the receptors for hematologic growth hormones must be stimulated.
COMFORT-1 showed 41.9% of patients on Ruxolitinib had spleen reduction  but in COMFORT-2, only 28% had spleen reduction by week 48.

The JAK inhibitors are now being tried in Pancreatic cancers!

*Obstruction to Cure is not only found in limitation of progress in science, but in man made complications such disparities in funding availability and managed care obstruction to access to known medications!  Cure escapes us for our own doing, in a summary!

*In Breast Cancer, Inhibitors to CD4,6 are proving to be a new approach when given with Letrozole

*In Prostate cancer don't be too eager to use Steroids with enzalutmide.  Steroids may "activate androgen receptors promoting the cancer".   I should confess this point is a bit controversial since that's what we do, stimulate to better kill with chemotherapy (Taxotere-Cabazitaxel).  But the logic may not work for another hormone used for killing.

*In Tivo-1,
they found no survival advantage for TIVOZANIB Vs Sorafenib in patient with Renal Cancer.
Tivozanib is said to be more potent and selective for VEGF receptors!  PFS was superior though with TIVO!

*Check this out!  The global multikinase inhibitor Regorafenib (blocks VEGFR1,KIT,TIE2,PDGFR and RET) got approved for GIST.  patients received 160 mg PO daily x21 Q28. Watch for fatigue hand foot sundrome diarrhea, loss of appetite,HTN,weight loss,rash and fever.  and being an anti-VEGF, bleeding and intestinal perforation of course!  rare cases of Coronary attacks!
*New kid on the block, RAMUCIRUMAB TRIED IN GASTRIC CANCER!

(READ TARGETED THERAPY NEWS)

* A new study suggests that Maintenance Docetaxel increases significantly progression survival: "Single-dose monthly maintenance treatments for a total of up to 12 months were offered to patients who had a complete response. Median time to recurrence was 39.3 months in responders treated with maintenance docetaxel, compared with 19 months in those who did not receive maintenance therapy.<sup>"(Medscape)

*READ IT1</sup>

"Radiolabeled Small Molecules Show Promise in Prostate Cancer Early Detection

By Zach Hartman | March 20, 2013

---

Radiolabeled small molecules targeting prostate-specific membrane antigen (PSMA) are well-tolerated tools for detection of metastatic prostate cancer, according to data published in the March 2013 issue of the Journal of Nuclear Medicine."

*Lymphoseek FDA approved for detection of metastatic disease involving the lymph nodes for Breast cancers and Melanoma!

GENES IN PROSTATE CANCERS

In a man, there is a 1/3 chances that if found with cancer, it will be prostate cancer.  But only in 10 percent of those who are dying and who have prostate cancer is it this cancer that causes death.  Meaning a number of patients with prostate cancer will die of another cause.   Over 186,000 men were diagnosed with Prostate Cancer and close to 29,000 died of this disease yearly. A 6.5 to 1 ratio.  This point to a heterogeneous disease, and we will fail by not stating (infamous statement) that autopsy showed that in men over 80 years of age, over 70% will be found with Prostate Cancer.  As if it was part of aging.   By aging, you implicate Telomeres and most likely the MTOR.
Before jumping to the MTOR which is cool lately, there is one overwhelming phenomena, that is the Prostatic cell development is significantly dependent on Testosterone for its growth.  And we have in our armamentarium many agents to stop Testosterone.  As we will suggest and as achieved for many hormones, Testosterone blockage can be completed at the cell level, in the testicles, in the Adrenal gland as well as by blocking it in the Pituitary stalk. It is not until one develops refractoriness to Androgen that one may die of Prostate cancer as the principal cause of death.  So the physician's task is to keep coming up with new strategies to block the Androgens.  There lies the key to treating Prostate Cancers.

THE REVERSAL OF FORTUNES
=========================
It is widely accepted that a small numbers of cells in the prostatic cancer mass (may be less than one percent at onset) will be mutated or spontaneously refractory to Androgen.  As time goes by, more mutations related or not to treatment, will occur, while hormone sensitive cancer cells are being starved from stimulation.  Over time, the refractory cells will grow in importance and drive the life of the tumor and metastasize everywhere replacing the hormone sensitive one. The disease will therefore become non responsive to Hormone and here comes patient rapid deterioration as the malignant tumor now adopts a new pattern of behavior including new locations of metastasis.  Liver lesions, lung lesions and Brain invasion becomes more likely to occur.   Chemotherapy with Taxane and Cabazitaxel, a derivative of natural Taxoids, become the mainstay of treatment.  ( Particularly now that Sipuleucel-T  is advanced to before chemotherapy) Keeping in mind that the reversal of fortune is change of proportions, there is still a portion of hormone responsive cells and Lupron needs to continue while chemotherapy is given!

PSA, Prostate Specific Antigen
======================
Prostate cancer is actually one of the rare diseases that can be screened effectively, and found early by a blood test.  That is until we realize that finding a disease that may not kill early leads to unnecessary treatment and patient futile mental disturbance in many cases.  We are now retracting, pulling back on our toes and people are growing reluctant to be tested. That is until we clarify what it is we should be looking for to make sure we discern who needs therapy! We needs to know who needs an early intervention.  For this the tumor needs to tell us I am bad, and we need to catch the message.  And most researchers believe Genetic profiling is one of the critical approaches  to tell the difference. The challenge is that Adenocarcinoma seems to follow a progression in their deterioration to a full blown cancer.  And some genes are present in prostatitis, Benign Prostatic hypertrophy, Low Gleason prostatic cancer and high gleason cancers.   Now which one makes it a bad cancer.  This is the current challenge but it will clearly open the door to Target therapy!

Molecular basis of Prostatic cancer Pathogenesis.

While dealing with Intraepithelial Atypical lesion, the presence of Alpha-Methylacyl-Coenzyme Aracemase is considered a signature of Adenocarcinoma presence!   In our discussion on Choriocarcinoma, we suggested that Hypermethylation is a major Knockdown way for E2.  It plays a role here too!   And gene fusion is the other abnormality that is a prominent phenomenon TMPRSS2 and ETS fusion (or TMPRSS2-ERG), and things" degenerate" from there !

Also note that the Androgen receptor gene is located on Xq11-13, (note the "q")

GENES in Prostate Cancers! (TO BE DEFINITELY CONTINUED)

DRUGS ON THE MOVE

 DRUGS  ON THE MOVE

1.   In Breast cancer

-Everolimus
-Pertuzumab
-T-DM-1

2.   In Prostate  cancer

-Abiraterone (Zytiga)
-Enzalutmide (Xtandi)
-Alpharadin (Radium 223)

3.   Other
-Cabozantinib
-Orteronel
-Curtisen
-Tasquinimod

4.   Melanoma

-Dabrafenib
-Trametinib
-GDC- 0973
-Vemurafenib (Zelboraf)
-Nivolumab
-Ipilimumab
-MK3754

5.   Lung cancers

-Crizotinib
-Afatinib
-Dacomitinib
-Nivolumab
- Selumetinib

5.   Thyroid cancer

-Pazopanib

ADVANCES IN PROSTATE CANCER

In advanced prostate cancer TREAT FIRST LINE WITH PROVENGE TO EXTEND SURVIVAL

Prescribing Information

PROVENGE extends median survival beyond 2 years in patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer PROVENGE reduced the risk of death by 22.5% vs the control group (P=0.032)¹

Overall Survival Benefits of PROVENGE1,2

Data originally published in The New England Journal of Medicine: Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. Average time to subsequent therapy with docetaxel in the IMPACT trial was approximately 1 year.¹

PROVENGE provides a sustained survival benefit and a durable immune response PROVENGE provided a survival benefit every year studied³

Overall Survival Benefit for PROVENGE3

*(Percent PROVENGE-percent control)/percent control.

Percentage of Patients Alive: ITT Population (95% CI)3 1 year 2 years 3 years 4 years PROVENGE 81.1% (76.9, 85.3) n=274 52.1% (46.4, 57.7) n=129 31.7% (25.7, 37.8) n=49 20.5% (14.0, 26.9) n=14 Control 72.4% (65.6, 79.1) n=123 41.2% (33.5, 49.9) n=55 23.0% (15.5, 30.5) n=19 16.0% (8.5, 23.4) n=4

ITT=intent-to-treat.

PROVENGE provided a durable immune response²

•  A sustained immune response to PROVENGE was seen out to 26 weeks in the pivotal study (the last time point measured)

PROVENGE provides a safety profile you and your patients can manage

Only 1.5% of patients treated with PROVENGE in the pivotal trial discontinued treatment due to adverse events²

The most common adverse events reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache²

INDICATION PROVENGE® (sipuleucel-T) is approved by the FDA as an autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

IMPORTANT SAFETY INFORMATION PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence ≥ 15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Please see the Full Prescribing Information.

Visit www.PROVENGE.com to learn more about treating advanced prostate cancer

REFERENCES

1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. PROVENGE [package insert]. Dendreon Corporation; June 2011. 3. Data on file. Dendreon Corporation.

©2012 Dendreon Corporation. All rights reserved. P-A-10.12-281.00