Vitamin A Compound Might Aid in Colon Cancer Fight

In continuation of my update on Retinoic acid

Retinoic acid, a compound derived in the body from vitamin A, might have a role in suppressing colon cancer, new animal research suggests.

"Retinoic acid has been known for years to be involved in suppressing inflammation in the intestine," said study senior author Dr. Edgar Engleman, professor of pathology and medicine at Stanford University School of Medicine in Palo Alto, Calif.

Meanwhile, the development of colon cancer has been linked to inflammation. For example, inflammatory bowel disease, such as ulcerative colitis, has been associated with colon cancer, he said in a university news release.

"We wanted to connect the dots and learn whether and how retinoic acid levels directly affect cancer development," Engleman added.

When the researchers looked at mice with colon cancer, they saw lower levels of retinoic acid in the intestines of the mice.

The researchers also found that boosting levels of retinoic acid in the intestines of mice with colon cancer slowed progression of the disease.

In humans, colon cancer patients who had high levels of a protein that degrades retinoic acid in their intestinal tissue tended to have worse outcomes than other patients, the study authors noted.

The findings suggest new ways to prevent or treat colon cancer. However, it's important to note that animal research doesn't always produce the same results in humans.

"The intestine is constantly bombarded by foreign organisms. As a result, its immune system is very complex," Engleman said.

"We found that bacteria, or molecules produced by bacteria, can cause a massive inflammatory reaction in the gut that directly affects retinoic acid metabolism," he said.

He said that retinoic acid levels are normally regulated very tightly.

"Now that we've shown a role for retinoic acid deficiency in colorectal cancer, we'd like to identify the specific microorganisms that initiate these changes in humans. Ultimately we hope to determine whether our findings could be useful for the prevention or treatment of colorectal cancer," he concluded.

The study was published online Aug. 30 in the journal Immunity.

Retinoic acid may provide relief for ulcerative colitis !

We know that Retinoic acid is the oxidized form of Vitamin A. It functions in determining position along embryonic anterior/posterior axis in chordates. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages. Retinoic acid acts by binding to heterodimers of the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), which then bind to retinoic acid response elements (RAREs) in the regulatory regions of direct targets (including Hox genes), thereby activating gene transcription.

Recently when I was reading a paper, found this interesting fact that is "retinoic acid, could be a beneficial treatment for people suffering from ulcerative colitis and other irritable bowel diseases. Specifically the researchers found that retinoic acid helps suppress out-of-control inflammation, which is a hallmark of active ulcerative colitis.

Pharmaceutical strategies based on this research may offer a promising alternative to the current approaches of managing immune diseases including, IBD, arthritis, multiple sclerosis, and so on, Aiping Bai, a researcher involved in the work from Nanchang University in Nanchang City, China claimed.

The studies ultimately found that treatment with retinoic acid reduced the inflammation in the colon by increasing the expression of FOXP3, a gene involved with immune system responses, as well as decreasing the expression of IL-17, a cytokine believed to cause inflammation. Because many experts believe that IL-17 directly relates to the uncontrolled inflammation seen in ulcerative colitis and irritable bowel disease, the discovery that retinoic acid reduces IL-17's ability to cause inflammation could accelerate the development of treatments for these chronic diseases.

Ref : http://www.jleukbio.org/cgi/content/abstract/86/4/959?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Aiping+Bai&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

Synthetic derivative of Retinoic acid can induce cell death

Retinoic acid (RA), a natural derivative of vitamin A, is the basis of a number of treatments against cancer. Nevertheless, it has certain disadvantages, such as the possibility of the appearance of retinoic acid syndrome, present in 25 % of cases and which can lead to death. The development of 4-HPR (see structure -Fenretinide 4-hydroxy(phenyl)retinamide) a synthetic derivative of RA, has meant a considerable advance due to its greater efficacy compared to its predecessor. It is able to induce the death of tumour cells as the method for reducing their proliferation, in a precise manner and without serious damage to surrounding tissue. Moreover, it halts the referred-to retinoic acid syndrome and even functions with cells that resist RA. In vitro studies corroborate its effectiveness as a chemopreventive agent and also as a chemotherapeutic agent, both with leukaemias and with ovary, breast or brain tumour cells.

Biologist Ms Aintzane Apraiz studied the 4-HPR in depth, focusing on the causes that, according to previous research, give rise to this ability to induce cell death. To this end, she applied this synthetic derivative to acute lymphoblastic leukaemia T cells (LLA-T). Her PhD thesis, defended at the University of the Basque Country (UPV/EHU), is entitled Role of sphingolipids and oxidative stress in the antineoplasic activity of 4-HPR: study in a leucemia model.

Amongst the various processes that can induce cell death, in the case of 4-HPR, apoptosis is outstanding; a precise mechanism and without inflammatory processes or serious damage to surrounding tissue. According to Ms Apraiz, previous research on LLA-T undertaken by the team of which she is a member, showed that 4-HPR induced a massive accumulation of ceramides (lipids of the cell membrane) and of reactive oxygen species (ROS), both of which can cause cell death. 

More...

Immunotherapy and Chemotherapy Regimen May Prolong Survival in Advanced Cancers

In continuation of my update on interleukin and retinoic acid

Cancer patients who receive a combination of low-dose interleukin-2 and retinoic acid after conventional therapy seem to live longer than those who don't get the combination. 

Retinoic acid is derived from vitamin A. Interleukin-2, a compound that fortifies the immune system, is approved at high doses to treat "metastatic" melanoma and kidney cancer. Metastatic means that a cancer has spread.

The study showed that "these biological compounds may work at low doses. Bigger doses are not always better," said lead author Dr. Francesco Recchia, director of the oncology department at Civilian Hospital in Avezzano, Italy.

Recchia stumbled upon the possibility of using low-dose interleukin-2 (IL-2) when he switched a patient with metastatic melanoma who didn't tolerate high doses to a lower dose, and the patient had an extended response to the therapy.

This study involved 500 patients who had already responded well to chemotherapy. They had a variety of cancers, including ovarian, lung, colon, stomach, kidney, melanoma, breast and pancreatic.

Immunotherapy and Chemotherapy Regimen May Prolong Survival in Advanced Cancers

Cytrx’s tamibarotene achieves molecular complete remission in advanced acute promyelocytic leukemia..

CytRx Corporation, announced that a 44-year-old female patient with advanced acute promyelocytic leukemia (APL) achieved molecular complete remission with no evidence of disease in the blood cells and/or bone marrow following treatment with CytRx's oncology drug candidate tamibarotene (see structure, an orally active, synthetic retinoid, developed to overcome all-trans retinoic acid (ATRA) resistance, with potential antineoplastic activity. As a specific retinoic acid receptor (RAR) alpha/beta agonist, tamibarotene is approximately ten times more potent than ATRA in inducing cell differentiation and apoptosis in HL-60 -human promyelocytic leukemia cell lines in vitro.). 

"This event represents a very significant milestone for CytRx and our drug candidate tamibarotene. Tamibarotene has saved a life and nothing can compare with that," said CytRx President and CEO Steven A. Kriegsman. "These important results indicate that tamibarotene warrants further evaluation as a third-line treatment and in combination as a first-line treatment for APL. We are also considering developing tamibarotene for other cancers as well.

Previously published reports indicate that tamibarotene is 10-times more potent and may be better tolerated than all trans retinoic acid (ATRA). Researchers believe that the combination of tamibarotene and arsenic trioxide (ATO) could produce a complete response rate similar to the ATRA and ATO combination with fewer toxicities such as APL differentiation syndrome.  The company is currently conducting a dose escalation trial combining tamibarotene with ATO as an important step in their ultimate goal of evaluating tamibarotene as a first-line treatment for APL. The company claims that, In addition to maintaining a complete remission six months following the last dose, tamibarotene was also well tolerated. In the CytRx's STAR-1 registration trial, patient was treated with tamibarotene for 56 days at the Department of Biopathology at the University of Rome 'Tor Vergata'. A molecular complete remission in the bone marrow was documented at the end of the treatment period and again six months following the last treatment with tamibarotene...

Ref ; http://www.cytrx.com/tamibarotene.html

FDA Approves Aklief (trifarotene) Cream, a New Topical Retinoid for the Treatment of Acne

Galderma, a global leader focused on meeting the world's increasing skin health needs, announced today that the U.S. Food and Drug Administration (FDA) approved Aklief (trifarotene) Cream, 0.005% for the topical treatment of acne. Aklief Cream is the only topical retinoid that selectively targets retinoic acid receptor (RAR) gamma, the most common RAR found in the skin.1,2,3 Trifarotene is the first new retinoid molecule to receive U.S. FDA approval for the treatment of acne in more than 20 years.4,5,6 Aklief Cream is the first topical treatment specifically studied and proven to treat both facial (forehead, cheeks, nose and chin) and truncal (chest, shoulders and back) acne, offering healthcare professionals and acne patients another treatment option.

"While retinoids are foundational therapies to treat acne, there has been little innovation in decades.” said Sandra Johnson, M.D., FAAD, an investigator in the clinical trials of Aklief Cream and a dermatologist at Johnson Dermatology in Fort Smith, Arkansas. “With the approval of Aklief Cream, I am excited to offer my patients a unique, highly targeted retinoid that reduces inflammatory lesions on the face, back, chest and shoulders, that has also been shown to be safe and well-tolerated."

The FDA approval of Aklief Cream is supported by data from the two pivotal Phase 3 clinical trials of once-daily Aklief Cream in patients with moderate acne on the face and trunk.1 The two identical 12-week, randomized, multicenter, parallel group, double-blind, vehicle-controlled clinical trials of 2,420 patients showed that Aklief Cream significantly reduced inflammatory lesions as early as two weeks on the face and four weeks on the back, shoulders and chest compared to vehicle (p<0.05).1 Aklief Cream was well tolerated when used on the face, back, shoulders and chest.1 The most common adverse reactions (incidence >1%) included application site irritation, application site pruritus (itching) and sunburn.1 

“The approval of Aklief Cream underscores our ability to bring new active molecules to the community, and innovate even in well-established therapeutic classes. It is consistent with our intent to change the paradigm of how even the most common and frustrating skin diseases are treated, including acne,” said Thibaud Portal PhD, Galderma Global Vice President, Prescription. “We are pleased to add this new treatment option, with proven efficacy in facial and truncal acne, to our innovative and differentiated portfolio of acne treatments.”

Aklief Cream is expected to be available in the United States in November 2019. It will be provided in a 45 gram pump. Galderma is working closely with payers, providers and pharmacy benefit managers to ensure broad and rapid access to Aklief Cream. The company will also offer a patient savings card program, Galderma CareConnect*.

*Galderma CareConnect is only available for commercially insured or uninsured patients. Patients who are enrolled in a government-run or government-sponsored healthcare plan with a pharmacy benefit are not eligible to use the Galderma CareConnect Patient Savings Card.

 https://en.wikipedia.org/wiki/Trifarotene

Palovarotene drug may prevent multiple musculoskeletal problems linked with FOP

We know that, Palovarotene (R-667, RO-3300074) is a highly selective retinoic acid receptor gamma (RAR-γ) agonist that is under investigation as a potential treatment for fibrodysplasia ossificans progressiva (FOP), an ultra-rare and severely disabling genetic disease characterized by extra-skeletal bone formation (heterotopic ossification or HO) in muscle and soft tissues. 

Palovarotene2DACS.svg

Palovarotene is being developed by Clementia Pharmaceuticals and was granted Fast Track and orphan drug designations by the United States Food and Drug Administration for the treatment of FOP and Orphan Medicinal Product Designation by the European Medicines Agency (EMA) in 2014. Phase II clinical studies are currently underway

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New research in laboratory animals suggests that the drug palovarotene may prevent multiple skeletal problems caused by a rare but extremely disabling genetic bone disease, and may even be a candidate for use in newborn babies with the condition. Scientists at The Children's Hospital of Philadelphia, who previously repurposed the drug to prevent excess bone formation in animal models of fibrodysplasia ossificans progressiva (FOP), have extended that research in animals carrying the exact human disease-causing mutation.

In humans with FOP, an activating mutation in the ACVR1 gene triggers extraskeletal cartilage and bone formation and accumulation starting in early childhood. The extraskeletal bone occurs in muscles and other tissues where it does not belong. This pathological process, collectively called heterotopic ossification (HO), causes progressive loss of skeletal motion and hampers breathing and swallowing.

Currently untreatable and painful, FOP often causes death early in adulthood.

"This work represents a big step toward therapy," said co-study leader, Maurizio Pacifici, Ph.D., a developmental biologist and director of Orthopedic Research in the Division of Orthopedic Surgery at The Children's Hospital of Philadelphia (CHOP). "The mice used in this study were engineered to carry the human mutation that causes FOP, and the drug showed powerful and comprehensive benefits for skeletal growth and function in addition to inhibiting HO. If these results translate to humans, we may be able to treat children with FOP early in life, before the disease progresses."

The research appeared online March 12 in the Journal of Bone and Mineral Research.

Palovarotene drug may prevent multiple musculoskeletal problems linked with FOP: New research in laboratory animals suggests that the drug palovarotene may prevent multiple skeletal problems caused by a rare but extremely disabling genetic bone disease, and may even be a candidate for use in newborn babies with the condition.