Author Archives: Emily Burke, Ph.D., Director of Curriculum Development, BiotechPrimer.com

The Multiple Myeloma Landscape

Editor’s Note: This article originally appeared in Biotech Primer Weekly. For more of the science behind the headlines, please subscribe.

Emily Burke, BiotechPrimer.com

Multiple myeloma is a cancer formed by a type of white blood cell called a plasma cell. These cells are the antibody-producing cells of our immune system and play a critical role in our defense against infections. If they begin to grow and divide in an uncontrolled manner, however, they form a plasmacytoma – a mass of cells within the bone marrow that no longer function in our defense but instead simply take up space and interfere with the functions of healthy cells. Instead of producing normal disease-fighting antibodies, plasmacytoma cells produce abnormal antibodies called M proteins, which don’t provide any benefit to the body and crowd out normally functioning antibodies.

Easily Confused: Plasma Cells vs Blood Plasma

Plasma cells are specialized white blood cells that produce infection-fighting antibody proteins. Most plasma cells are found in the bone marrow. Blood plasma is the straw-colored liquid component of blood that holds blood cells in suspension, made up of water (95%), proteins, glucose, clotting factors, electrolytes, hormones, carbon dioxide, and oxygen.

Picking Apart Plasmacytoma

Plasmacytoma formation can lead to a host of problems with recognizable clinical symptoms. Because all blood cells are formed in the bone marrow, over-production of plasma cells can essentially “crowd out” normal blood-forming cells. This can lead to anemia, caused by a shortage of oxygen-carrying red blood cells; increased bruising and bleeding due to a reduction in clot-promoting platelets; and an increased risk of infections due to lower levels of healthy infection-fighting white blood cells.

Although multiple myeloma is classified as a blood cancer, it has a significant impact on bone health. As the plasmacytoma grows, bone-forming cells called osteoblasts are suppressed. At the same time, production of a substance that activates bone-reabsorbing cells, osteoclasts, is increased. The resultant damage to the bone structure results in soft spots or lesions which may extend from the inner bone marrow to the outside surface of the bone. Bone lesions result in significant pain and increase the risk of fracture. Bone destruction also releases excessive calcium into the bloodstream, which leads to a range of symptoms including changes in urination, restlessness, confusion, increased thirst, nausea, and loss of appetite. Excess blood calcium, combined with high levels of M protein, also contributes to the impaired kidney function seen in multiple myeloma patients.

Unmasking Multiple Myeloma

There is no one diagnostic test for multiple myeloma. Blood and urine tests to detect some of the symptoms listed above such as low blood cell counts, elevated blood calcium levels, and impaired kidney function may suggest multiple myeloma. These tests can be followed by a bone marrow biopsy for confirmation.

Most cases of multiple myeloma have no known cause, although some research suggests that regular exposure to herbicides, insecticides, petroleum products, heavy metals, and asbestos increases the risk of developing the disease. And although there is not a specific gene yet associated with multiple myeloma, abnormalities in chromosome structure or number are associated with the disease.

Multiple Myeloma Treatments

Once considered incurable, there are now a number of effective treatments for multiple myeloma, and several more are in the pipeline.

Currently, there are two FDA-approved monoclonal antibody therapeutics approved to treat multiple myeloma.  They work by recognizing and binding to proteins on the surface of multiple myeloma cells, activating the patient’s immune system to destroy those cells.

Another type of approved therapy for multiple myeloma is a small molecule proteasome inhibitor therapy. A proteasome is a specialized compartment within the cell that gets rid of damaged proteins by digesting them. If the proteasome is inhibited, damaged proteins build up within the cell. This triggers a process called apoptosis – essentially, cell suicide. In other words, the cancer cell kills itself.

Small molecule histone deacetylase (HDAC) inhibitors have also been shown to be safe and effective in treating multiple myeloma. HDACs are enzymes that modify chromosomes (strands of DNA that contain our genes) and influence how often specific genes are activated. Some cases of multiple myeloma are associated with changes in gene activation. By inhibiting HDACs, this faulty gene expression can be corrected.

In the Pipeline

Two novel drugs in the multiple myeloma pipeline are Mivebresib and Selinexor.

Mivebresib influences the activation of specific genes by inhibiting a group of proteins called Bromodomain and Extra Terminal motif (BET) proteins. In some types of cancer, genes are activated or deactivated inappropriately due to BET activity. By inhibiting BET, normal gene activity may be restored to these cells.

Selinexor helps to increase the number of tumor suppressor proteins present in the nucleus of cancer cells. These proteins help to protect against cancer by detecting DNA damage and promoting apoptosis in those cells that have high levels of DNA damage. In many types of cancer cells, tumor suppressor proteins are transported out of the nucleus, where they can no longer do their job of detecting DNA damage. Selinexor blocks this transport and enables tumor suppressor proteins to do their job of triggering apoptosis in cancer cells.

A number of CAR-T therapies are also in development for multiple myeloma, with several early stage clinical trials ongoing. 

Multiple myeloma is a complex type of cancer. In recent years, a better understanding of the disease has led to the approval of several new therapeutics. In the coming years, we can look forward to additional approvals as novel therapeutics move through the pipeline.

The Mechanics of Melanoma

May is Melanoma Awareness Month. This article originally appeared in the Biotech Primer WEEKLY. For more on the science behind the headlines, subscribe. 

Melanoma 101 

Emily Burke, BiotechPrimer.com

Melanoma accounts for less than one percent of skin cancer cases, yet accounts for the vast majority of skin cancer deaths (skincancer.org). If detected early enough, melanoma is almost always curable. If it is not detected early, it is likely to spread to other parts of the body, where it is more difficult to treat. It’s estimated that in 2017, there will be 87,110 new cases of melanoma in the U.S., and 9,730 melanoma-related deaths (Aim at Melanoma Foundation). Melanoma is one of the types of cancers most common in young adults, with 25 percent of new cases occurring in people under age 45. Its prevalence is growing – the number of new cases/year relative to the total population has doubled since 1973.

In this column, we’ll review the basics of melanoma, and discuss the latest new therapies recently approved and in development.

Melanoma’s Method

Melanoma is the uncontrolled growth of the pigment-producing cells known as melanocytes, which are located in the bottom layer of the skin’s top layer (the epidermis). Like other types of cancers, melanoma arises from gene mutations in these cells that impact cell growth and division. In the case of melanoma and other skin cancers, the DNA damage is usually caused by ultraviolet (UV) radiation, resulting in a tumor that initially grows in the skin, spreading along the epidermis. If the melanoma is detected at this stage, it can often be surgically removed. If the out of control cell growth is not caught in these early stages, it penetrates deeper layers of the skin, eventually coming into contact with lymph and blood vessels which enable it to spread to other parts of the body. When the melanoma reaches this stage, it is called metastatic melanoma.

Although anyone can get melanoma, fair-skinned people are at higher risk for all types of skin cancer, since increased skin pigmentation helps to block the damaging UV rays from penetrating and damaging skin cell DNA. However, darker-skinned people can and do get skin cancer, and thus should also be vigilant about sun protection.

Atypical moles have also been linked to an increased risk of melanoma. Moles are clusters of melanocytes, and there is a slightly increased risk of melanoma arising within these clusters. Of course, most moles are harmless and do not lead to melanoma. However, any sudden changes in the color, shape, or size of a mole should be evaluated by a doctor.

Genetic Factors: p53 & BRAF 

Although most cases of all types of skin cancer are traceable to excessive sun exposure, about 10% are likely due to genetic factors. The gene most commonly mutated in familial melanoma is p53. p53 is a “tumor suppressor,” which means that it detects DNA damage in cells, and triggers either DNA repair pathways or activates cell death if the DNA damage cannot be repaired. Another gene, known as the BRAF gene, regulates cell growth and is mutated in inherited forms of melanoma. About half of all genetically-based melanomas have the BRAF mutation.

Let’s take a closer look at BRAF. BRAF codes for a protein required for the transmission of a growth signal from a cell surface receptor to the cell nucleus (growth signal transduction). Growth signaling is initiated by a growth factor binding to its receptor. This binding transmits a signal through the membrane, causing the internal portion of the receptor to interact with and activate a protein inside of the cell. This activation is then transferred to the next protein in the pathway, and so on until the signal reaches the last protein in the pathway. When this protein is activated, it enters the nucleus, where it turns on specific genes that make proteins which initiate cell division. BRAF is one of the proteins in this pathway. In BRAF-associated melanoma, the mutated BRAF is always turned on even when no growth factor is present.

Small molecule drugs that inhibit overactive BRAF have been developed and approved for the treatment of late-stage melanoma.

Immunotherapies in the Fight 

A few different checkpoint inhibitor therapies have been approved to treat metastatic melanoma. These are drugs that enable killer T-cells – immune system cells that recognize and kill threats such as cancer cells – to become fully active against a tumor cell target. These drugs target inhibitory proteins on the surface of T-cells such us CTLA-4 and PD-1. These proteins act as “off switches” for killer T-cells. By inhibiting these off switches, the killer T-cells become fully activated, and able to target and kill melanoma cells.

A second type of immunotherapy that has been approved for melanoma is an oncolytic virus therapy. An oncolytic virus is a virus that infects and kills cancer cells. The cancer cells are killed through cell lysis – as the virus multiplies inside of the cells, it causes them to burst open. This in turn releases new infectious particles that can target remaining tumor cells. In addition to direct killing of cancer cells via lysis, the presence of an actively replicating virus helps to activate the patient’s immune response to target the area.

In the Pipeline 

A new type of immunotherapy drug is in Phase 3 clinical development. The drug is a small molecule inhibitor of the enzyme IDO1. IDO1 helps regulatory T-cells to develop and become activated. Regulatory T-cells suppress the immune response, and therefore help cancer cells to escape immune surveillance. Inhibiting IDO1 should suppress the development of regulatory T-cells, bolstering the immune response against melanoma.

Implications of microRNA 

Last year, researchers at Tel Aviv University published a report describing how melanoma metastasizes. Their work suggests that melanoma cells release tiny vesicles that contain microRNA, a type of regulatory RNA produced by all cells. These micro-RNA filled vesicles induce changes in the dermis – the layer of skin just below the epidermis where the melanoma begins. The dermis contains blood vessels, and thus a pathway for metastasis. The changes in the dermis induced by the small vesicles released from the melanoma cells makes the cancer cells able to access those blood vessels. The Tel Aviv team is identifying drug candidates that may interfere with this process, preventing the metastasis that makes melanoma so deadly.

The best strategy for melanoma remains prevention and proactive monitoring – limiting sun exposure and monitoring the skin for any unusual growths or changes in moles. Increased understanding of the molecular pathways that contribute to melanoma’s development and spread will provide physicians with additional tools to fight those cases of metastatic melanoma that inevitably will continue to arise.

Categories: General, Melanoma

A Big Pain

Editor’s Note: This article in our pain management series originally appeared in Biotech Primer Weekly. For more of the science behind the headlines, please subscribe.

The Science Behind Opiods

Emily Burke, BiotechPrimer.com

The opioid addiction epidemic gained attention at the highest levels of U.S. policy circles this past year, as presidential candidates that disagreed on nearly everything else vowed to make fighting the problem a priority if elected. In July, the U.S. Senate overwhelmingly approved a bill to strengthen prevention, treatment, and recovery efforts. And no wonder – according to the Center for Disease Control, opioid overdose deaths are at an all-time high – a stark reality that highlights the dark side of a class of treatments serving a vital need. Opioid pain medications manage the severe short-term or chronic pain of millions of Americans. While these medications mitigate needless suffering, joining forces are the government, corporations, and medical community to battle against opioid abuse and addiction.

We wonder: what is the science behind the headlines? So, let’s talk about how pain medications work, the different types on the market, and the approaches to developing less addictive versions of opioid drugs.

Opiods vs. NSAIDS

There are two main categories of pain medications, opioids and non-steroidal anti-inflammatory drugs (NSAIDs). Although these two categories of drugs work differently, they do share one thing in common: both are derivatives of natural products. The NSAID Aspirin is a synthetic version of an extract from willow tree bark, and opioids are synthetic versions of opium and morphine, which come from poppy flowers.

Aspirin works by inhibiting an enzyme called cyclooxyrgenase 1 (COX-1). Once stopped, COX-1 is no longer able to produce signaling molecules, called prostaglandins and thromboxanes. Prostaglandins and thromboxanes have a wide variety of functions, including mediating aspects of inflammation (fever and swelling) as well as promoting neuronal response to pain. Other NSAIDs, such as ibuprofen and naproxen, also work by inhibiting COX-1 or its sister enzyme COX-2.

Opioid pain medications, such as Oxycontin and Percocet, work by binding to mu receptor proteins on the surface of cells in the central nervous system (CNS) —think brain and spinal cord. While the CNS is tasked with relaying pain signals, opioids decrease the excitability of nerve cells delivering the message, resulting in pain relief—along with a feeling of euphoria in some users. 

Lessening the Pain

Short term medical used of opioid pain killers rarely leads to addiction—when properly managed. Due to the euphoria-inducing effects of the drugs, long-term regular use, or use in the absence of pain, may lead to physical dependence and addiction. And because regular use increases drug tolerance, higher doses are required to achieve the same effect, leading abusers to consume pain pills in unsafe ways such as crushing and snorting or injecting the pills. According to the Centers for Disease Control, 44 Americans die every day due to prescription painkiller overdose. At the same time, chronic pain is also a serious problem, affecting approximately 100 million U.S. adults, while millions of others suffer acute pain due to injury or surgery. The medical need for these drugs is very real despite the dark side.

The answer to developing less addictive drugs may be found in a drug that blocks pain without inducing euphoria. These new drugs will need a different mechanism of action than traditional opioid drugs, which bind to the mu receptors of cells inside the CNS. Drugs under development include those that bind to a different type of opioid receptor, the kappa opioid receptor. These receptors are present on sensory nerves outside of the CNS.

Preclinical studies suggest that targeting these receptors could be effective at reducing pain without driving addictive behaviors. A lead candidate, CR845, is currently in Phase 3 clinical testing for post-operative pain and pruritus (severe itching), and in Phase 2 clinical testing for chronic pain. Also under development are compounds that selectively activate cannabinoid (CB) receptors outside of the CNS. CB receptors inside the CNS are linked to the psychoactive qualities of marijuana; those outside the brain are found on white blood cells and have been shown to be involved in decreasing pain and inflammation. A lead CB receptor activator, CR701, is in preclinical development.

Also under development are small molecule inhibitors of ion channels – proteins on the surface of nerve cells that help to transmit pain signals by allowing positively charged calcium ions to enter the nerve. This plays a critical role in sending the pain signal to the brain, yet because it works on nerves outside of the brain, it has less of a potential for addiction.  Phase 1 clinical studies are currently underway of HX-100 for the treatment of painful diabetic neuropathy.

Another development is a derivative of capsaicin, a naturally-occurring compound found in chili peppers. Capsaicin has pain relieving properties and has been used as a natural remedy. The lead candidate, CNTX-4975, is a highly potent, synthetic form of capsaicin designed to be administered via injection into the site of pain. CNTX-4975 targets the capsaicin receptor, an ion channel protein on the surface of nerve cells. When CNTX-4975 binds the capsaicin receptor, the influx of calcium ions results in desensitization of the nerves, making them unresponsive to other pain signals. This effect can last for months, and only affects nerves near the site of injection. CNTX-4975 is currently in Phase 2b clinical studies for knee osteoarthritis, and Phase 2 clinical studies for Morton’s neuroma, a sharp pain in the foot and toe caused from a thickening of the tissue around one of the nerves leading to the toes.

Earlier this year, researchers at Tulane University published a paper that shows great promise for the development of effective yet non-addictive pain medications. They have developed a compound that is derived from the endogenous opioid endomorphin. Endogenous opioids are chemicals produced naturally by the body that bind to and activate the mu opioid receptors, resulting in pain relief and mild euphoria without the detrimental side effects associated with opioid drugs such depressed respiration, motor impairment, and addiction. Scientist have tried before to develop safer pain medications based on endogenous opioids, but have not been successful, due to the instability of these molecules. The Tulane team created a derivative of endomorphin that is stable and binds to the mu receptor in such a way that pain relief occurs, but not the negative side effects listed above. Clinical testing is expected to begin by the end of 2017.

An Antidote to an Overdose

Overdosing can be fatal since respiratory failure occurs at high blood concentration levels of opioids. If an overdose is suspected, the individual should be treated as quickly as possible with naloxone—a “competitive antagonist” of the mu opioid receptor. Simply put, a competitive antagonist binds the receptor without activating it. Since naloxone doesn’t activate the receptor, it doesn’t have any pain-relieving or euphoria-inducing qualities; rather, it prevents the opioid drugs from binding. It may also displace opioids that have already bound the mu receptor, aiding in the stoppage of an overdose.

Cocktail Fodder: Runner’s High

Some folks love to run; others avoid it at all costs. This might be explained by inherent differences in sensitivity to the natural opioids called endorphins that are released during exercise. Not everyone experiences the “runner’s high” — feelings of calm and mild euphoria – just like not everyone experiences euphoric feelings from pain medications. These differences may help to explain why some people enjoy exercise and others don’t, and why some people get addicted to opioids—while others can take them or leave them.

 

Breaking Down Lung Cancer

Editor’s Note: This article originally appeared in Biotech Primer Weekly. For more of the science behind the headlines, please subscribe.

Emily Burke, BiotechPrimer.com

Emily Burke, BiotechPrimer.com

The hit TV series Breaking Bad featured anti-hero Walter White, who starts out as a sympathetic character: a mild-mannered high school chemistry teacher with a nagging cough that turns out to be lung cancer. Money problems precipitated by costly treatments, poor insurance, and a modest salary push him to start cooking up meth to ensure the financial security of his family. The treatments succeed beyond his expectations, restoring his health long enough for him to become an unexpected meth kingpin.

Breaking Bad is a fictionally extreme example of the chaos that can arise from a lung cancer diagnosis. In fact, lung cancer is the leading cause of cancer-related deaths in the United States. Let’s take a closer look at the molecular causes, the different types, and some of the treatments available.

The Danger

While Walter White did not smoke cigarettes, 90 percent of those affected by lung cancer are smokers. Other causes of lung cancer include environmental or workplace exposure to carcinogens (known cancer-causing agents) such as radon, asbestos, or air pollution.

Smoking causes cancer because the inhaled smoke contains a range of chemicals, 70 of which are known to be carcinogens, including benzene, formaldehyde, methanol, and acetylene. Some carcinogens are genotoxic, meaning that they cause cancer by directly interacting with and damaging DNA. If that DNA damage occurs in a gene involved in regulating cell division, cancer may result. Non-genotoxic carcinogens have no direct interaction with DNA, rather they disrupt cellular structures and change the rate of either cell division or processes that increase the rate of genetic error.

Radon gas exposure can result in cancer because it is radioactive, and the high-energy radioactive particles given off as the gas decays can cause direct damage to cellular DNA. Radon gas is released from the normal decay of radioactive elements occurring naturally in soil and rocks. Radon is not considered dangerous because it is usually present at very low levels. However, it can sometimes build up to dangerous levels in well-insulated, tightly-sealed homes built on soil rich in uranium, thorium, or radium.

Asbestos used to be a common insulating material used in buildings and ships. The microscopic fibers in asbestos can be inhaled and become lodged in lung cells, triggering the activation of inflammatory pathways that result in the release of mutagens and factors that promote tumor growth. Since its hazards became well-documented in the mid-1970s, it is no longer used as insulation.

In addition to carcinogen exposure, there are likely genetic elements that make certain individuals more or less susceptible to lung cancer. Even though 90 percent of lung cancer cases are caused by smoking, only about 10 percent of smokers get lung cancer. In African-American populations, even when differences in smoking rates and access to healthcare are controlled for, the rates of lung cancer are higher. Both of these scenarios suggests that there may be genetic factors that make certain people more (or less) susceptible.

Small Cell

About 10 percent of lung cancer is small cell, meaning it occurs in the very small cells found in the bronchii—the tubes that branch off of the trachea, enter the lungs, and divide into even smaller branches within the air sac.

There are currently no targeted therapies available for small cell lung cancer, with chemotherapy and/or radiation as the main line of treatment. Broad ranging therapies that harness the immune system are in the pipeline.

Non-Small Cell

Cancer that occurs within any cell outside of small cells is referred to as non-small cell lung cancer (NSCLC), making up the majority (~90 percent) of lung cancer cases.

A number of drugs targeting new blood vessel growth—angiogenesis inhibitors—have been approved for the treatment of NSCLC.

There are also drugs that target specific NSCLC–associated mutations. For example, 10-35 percent of NSCLC cases are caused by the over-expression of the growth factor receptor EGFR. These types of NSCLC—more common in non-smokers—can be treated by drugs that target and inhibit this receptor. Asians are much more likely than other races to carry an EGFR mutation.

About five percent of NSLC cases are caused by mutations in a gene known as anaplastic lymphoma kinase (ALK). ALK proteins activate cell division, and mutated versions can drive cell division inappropriately. There are drugs currently on the market that inhibit ALK.

A checkpoint inhibitor drug has also been approved for NSCLC patients whose cancers start growing again after chemotherapy.

Cocktail Fodder: Walter’s Diagnosis

Diagnosed with NSCLC, Walter White specifically had an inoperable stage 3A adenocarcinoma. This means the cancer was initiated in the mucus-producing cells of the lungs and had spread to the lymph nodes (or other sites near the lungs), but had not spread to distant sites within the body. Some types of adenocarcinomas are caused by ALK mutations, so it is possible that Walter’s miraculous recovery was caused by an ALK inhibitor.

 

Attacking All Angles of Alzheimer’s

Editor’s Note: This article originally appeared in Biotech Primer Weekly. For more information on the science behind the headlines, please subscribe.

Emily Burke, BiotechPrimer.com

Emily Burke, BiotechPrimer.com

Alzheimer’s disease ranks as one of the toughest nuts to crack within drug discovery and development. Current treatments merely manage symptoms, so finding a better solution becomes more and more urgent as the aging population grows.

The pathology most commonly associated with Alzheimer’s disease (AD) is the buildup of amyloid-beta (Aβ) plaques in the brain. Recent research from Stanford University suggests the plaques bind to a receptor on nerve cells, disrupting their function. However, there is no absolute consensus that these clumps of protein are the origins of AD or a symptom of the underlying cause.

Most experimental drugs have focused on “mopping up” or inhibiting the production of Aβ plaques. Failures in early clinical trials dominate the treatment landscape, with a few potentials in the pipeline (aducanumab in Phase III). In the race to find a cure, every possibility offers a glimmer of hope, so let’s shine a light on the developmental drugs stepping away from Aβ plaques.

Loss of Neurons

A key clinical feature of AD patients is the loss of neurons. What if there was a therapy that could jump start the development of new neurons? Two companies are leading the charge in developing small molecule activators of neurogenesis. By screening large chemical libraries, they have identified various compounds that show promise in activating neurogenesis from adult neural stem cells, both in tissue culture and in mouse models.

In a mouse model of Alzheimer’s, compound NNI-362 promoted the growth of new hippocampal neurons that not only migrated to the correct functional location but also differentiated and survived long enough to reduce the previously observed cognitive declines. The hippocampus is thought to play a role in memory formation and spatial navigation and is one of the first regions of the brain to show damage in AD. Phase I trials for NNI-362 are currently in preparation.

Another neurogenesis candidate, NSI-189, increased the hippocampal region of mouse brains by as much as 20 percent. Phase I trials for NSI-189 were recently completed for major depressive order, with an aim to branch out to Alzheimer’s disease in the future.

Engineering Yeast Cells

Rather than directly targeting Aβ plaques, one group of researchers is working to identify their roots. By engineering yeast cells to produce the Aβ protein, this research is monitoring the detrimental downstream effects of over-expression — like the disruption in the folding of other essential cellular proteins. Compounds that show promise in the yeast cells are then tested in AD patient-derived cells to screen for potential drugs. The sponsor is currently preparing to begin clinical trials with its lead compound.

Neuroinflammation

Another company is bypassing Aβ plaques altogether and going after neuroinflammation. This pathway grew out of research conducted at Stanford, suggesting that a protein known as c1q is present in higher levels in the brains of AD sufferers. C1q accumulates at neuronal synapses, the key points of communication between brain cells. C1q also acts as a flag for other immune cells like macrophages — these “big eaters” chomp up cellular debris. The correlation of c1q could account for the observed reduction in synapse numbers and the accompanying loss of cognitive function seen in AD. The sponsor’s lead candidate, now in preclinical development, is a monoclonal antibody which “mops up” excess c1q.

Proteasomes

A partnership between two sponsors is targeting AD-associated protein aggregates by activating a cellular component known as the proteasome. Proteasomes get rid of damaged proteins and dysfunctional protein aggregates by dismantling the peptide bonds holding them together. USP14 is one of the proteins that inhibits the proteasome, so this work is focused on the preclinical development of a USP14 inhibitor to allow proteasomes to be fully activated in AD patients.

Attacking Alzheimer’s from all angles is the surefire way to get closer to better treatments and a real cure.

The Central Nervous System: A Brief Primer

The central nervous system (CNS) consists of the brain and the spinal cord. It sends and receives information from the peripheral nervous system—the vast network of nerves that feed into every tissue of the body. These signals enable voluntary and involuntary movement, and allow the brain to process and interpret sensory information sent from the spinal cord.

Emily Burke, BiotechPrimer.com

Emily Burke, BiotechPrimer.com

Specialized cells called neurons make up the CNS. Neurons send and receive signals electrochemically, meaning a chemical message is converted into an electrical signal within the neuron. When a chemical message (a neurotransmitter) reaches the edge of the neuron (the dendrite) the neurotransmitter causes ion channels in the cell membrane to open. This action allows positively charged sodium ions to enter sending a charge—an electrical signal—through the body of the neuron. The charge leaves through the neuron’s opposite side, another extension call an axon. This release causes other neurotransmitters to activate other neurons. Different neurons send and receive different types of neurotransmitters. Billions of neurons within the central nervous system communicate via 100+ different types of neurotransmitters. This neuron/neurotransmitter dual regulates just about everything within the human body from movement, to hunger, to body temperature, to emotion, and to wakefulness.

Not surprisingly, such a complex system—and the various diseases that affect it—are not entirely understood. Conditions that impact the CNS include infectious disease, genetic disease, cancer, stroke, and traumatic injury. In the next few paragraphs, we’ll take a closer look at four CNS diseases that are top research priorities.

Huntington’s Disease (HD)

Huntington’s disease (HD) is a neurodegenerative disorder— neurons progressively lose structure and function. As the disease continues and more neurons are damaged and die, symptoms get worse. Early stage patients may experience subtle involuntary movements and mood disturbances, but as the disease progresses, patients lose the ability to walk, speak, and swallow. Life expectancy is 20 years after onset of initial symptoms. 90 percent of HD cases affect adults between the ages of 30 and 50; juvenile onset occurs in the remaining 10 percent of cases.

HD is a monogenic disease, meaning it is caused by a mutation in one gene, dubbed the Huntington gene. The disease is also dominant. Everyone has two copies of each gene; for dominant genetic diseases, one mutated copy ensures the person will develop the disease, even if the other copy is correct. In practical terms, this means if an individual’s parent had HD, that individual has a 50 percent chance of developing it themselves. Because there is currently no cure for HD, some at-risk individuals may choose not to be tested for the gene. In fact, HD testing of people younger than 18 is prohibited, unless they are already showing symptoms of juvenile onset HD. This moratorium is to ensure that those tested understand the full implications.

Despite knowing the genetic basis of HD, scientists do not yet fully understand the disease mechanism. Recent advances in gene therapy and genome editing (fixing defective gene copies with functional copies) offer new hope for an HD cure. Replacing dead or damaged neurons with new neurons derived from stem cells is another approach under investigation.

Parkinson’s Disease

Like HD, Parkinson’s disease (PD) is a neurodegenerative disorder. In particular, PD patients have reduced activity and death of neurons that secrete the neurotransmitter dopamine. Typical symptoms of PD include motor disturbances such as tremors, slowness of movement, and rigidity, as well as a decline in cognitive function. Since PD primarily affects people over 60, as the Baby Boomer population ages, significant increases in PD are expected.

Parkinson’s is not a genetic disorder in the same sense that HD is—there is not a specific gene associated with it. In fact, the majority of cases are classified as “sporadic,” in other words, arising without a genetic association or apparent cause. Ongoing research into the disease involves teasing out genes that may indicate increased susceptibility. There is currently no cure for PD; however drugs that mimic the effect of dopamine have proven successful at managing some of the motor disturbances. Ongoing research also involves using stem cell-derived neuronal cells to replace dead or dying neurons.

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease in which the patient’s own immune system attacks and destroys the protective insulating layer known as the myelin sheath that surrounds the axon section of the neuron. This lack of myelin results in problems with the transmission of electrical signals from one neuron to the next.

MS typically strikes people in their early adult years. Initial symptoms vary widely, as they are dependent on the particular part of the CNS that is under attack, which can include motor, sensory, or visual problems. Initial symptoms are often highly intermittent, and might not reoccur for years. MS is a chronic, progressive disease, with symptoms gradually worsening over decades. Advanced patients are often confined to a wheelchair.

Like PD, there is no clear-cut genetic cause, although some genes have been identified as susceptibility genes, or genes that increase the odds of an individual developing MS. It is more common in women by a three to one ratio; this suggests that hormones play a role in susceptibility as well. Geography is also a factor—there is a higher incidence of cases the farther north one travels from the equator. Since sunlight is required for the sufficient production of vitamin D, it’s speculated that vitamin D may play a protective role in susceptible individuals. Likewise, in some cases it is thought that viral infections may trigger MS. The ultimate expression of the disease is likely the result of a combination of genetic and environmental factors.

Although there is no cure for MS, there are a number of drugs on the market that slow down its progression by blunting the immune system’s attack on the CNS.

Alzheimer’s Disease

Alzheimer’s disease (AD) accounts for approximately 70 percent of dementia cases. Like HD and PD, it is a neurodegenerative disease, with neurons in the hippocampal region of the brain associated with memory formation being among the first affected. By 2025, the number of people age 65 and older with Alzheimer’s disease is projected to reach 7.1 million—a 40 percent increase from the 5.1 million affected in 2015 (Alzheimer’s Association). Alzheimer’s disease is associated with the build-up of amyloid-beta (Aβ) plaques in patients’ brains.  But what, exactly, are Aβ plaques? Aβ plaques derive from the cleavage of a protein called the amyloid precursor protein, which is thought to play a role in the formation of synapses. Individual Aβ molecules clump together to form the plaques associated with Alzheimers’.

Until very recently, the mechanism by which Aβ plaques might cause Alzheimer’s was not known. Researchers at Stanford School of Medicine have recently demonstrated that Aβ binds to a receptor on nerves cells that disrupts the function of synapse.  This finding suggests a potential drug target: the ability to disrupt this interaction could preserve functioning nerve cells.

There is currently no cure for AD; however a number of different companies are working to develop treatments, with a few already in clinical trials. These potential treatments and the basic science that drives them will be covered in a future post.

The State of Cystic Fibrosis and Precision Medicine

EDITOR’S NOTE: This article is reprinted with permission from BioTechPrimer.com.

During President Obama’s State of the Union address earlier this year, a cystic fibrosis patient named Bill Elder sat beside First Lady Michelle Obama. Diagnosed with the disease at 8 years old, Mr. Elder is “healthier now than ever before” at age 27, thanks to ivacaftor. As a third-year medical student, he is not only surviving but thriving. Receiving an invitation to be the guest of honor at the presidential speech of the year is the exclamation mark to an extraordinary story.

Emily Burke, BiotechPrimer.com

Emily Burke, BiotechPrimer.com

Mr. Elder is an example of the success of modern medicine. His cystic fibrosis (CF) treatment derives from an understanding of the underlying molecular causes of the disease. This approach, referred to by the President as precision medicine, is the focus of new federal investments to speed the development of targeted therapeutics — drugs designed for a subset of patients with a specific genetic defect rather than for the “average” patient.

Personalized Medicine vs. Precision Medicine

Personalized medicine implies the development of medicines for an individual, based on their unique genetic, metabolic, microbiomic and other “signatures.” Think of a breast cancer patient getting a genetic test for the BRCA gene to determine their specific genetic mutation and subsequent personalized course of treatment — not just a therapy for all BRCA-induced cancers. As large scale, full-genome sequencing becomes more efficient and common, we may start to see truly personalized medicines.

But for now, a better term is “stratified” or precision medicine — dividing patient groups into specific populations and designing new drugs for those subtypes.

What is Cystic Fibrosis?

Cystic fibrosis is a genetic disease caused by one of several possible mutations in the gene encoding the “cystic fibrosis transmembrane conductance regulator” (CTFR) protein. The CTFR protein is critical for the production of sweat, digestive fluids and mucus. It affects around 70,000 people globally and is prevalent in America, Europe and Australia.

The CTFR protein is classified as a channel protein — a category of proteins that create a channel, or tunnel, across the cell membrane. This specialized gateway allows things to pass through the cell that will otherwise be denied entry or exit.

Negatively charged chloride ions use CTFR to exit cells, and if CTFR is not functioning correctly, the chloride ion builds up inside of cells. The build-up affects the fluid balance of tissue, which results in characteristically thick mucus seen in the lungs of CF patients. This thick mucus makes CF patients vulnerable to potentially fatal lung infections.

CF is an autosomal recessive disorder, meaning if an individual has one functioning copy of the CTFR gene, they are termed “carriers” and will not develop the disease. Two copies of the malfunctioning CTFR gene, one from each parent, will equal a diagnosis. And while CF is always caused by a mutation, many possible mutation combinations have been associated with the disease — up to 1,500 mutations, maybe more, are possible.

Precision medicine plays the hero by identifying the exact effect these underlying mutations have on CTFR, and designing treatments to overcome the disease.

On the Market

Cystic Fibrosis is symptomatically managed by reducing the risks of lung infections and implementing lifestyle changes to prevent such infections. Antibiotics are taken at the slightest sign of sickness, or even prophylactically, and other medications work to thin mucus. As the disease progresses, a double lung transplant may be the only, albeit elusive, treatment.

The dire medical outlook changed for a subset of CF patients in 2012 when ivacaftor, a small molecule drug, received FDA approval. Ivacaftor works by binding to the misfolded CTFR channel protein and increasing its ability to remain open and functional on cellular surfaces. It is indicated for few than 10% of CF patients; Mr. Elder is one of the lucky ones who responds to it.

With the success of ivacaftor, the manufacturer developed another small molecule drug, lumacaftor.

Approved by the FDA in July 2015, lumacaftor is paired with ivacaftor to target the most common CF mutation responsible for about 70% of the diagnosed CF cases in U.S. Caucasians. In these patients, the channel protein is so damaged it never makes it to the cell surface. Lumacaftor corrects some of the misfolds, improving CTFR’s ability to travel to the cell surface.

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Targeting Breast Cancer: The Subtypes of Breast Cancer

Editor’s Note: Based on an article originally published in Biotech Primer Weekly.

Hearing your doctor utter the words HER2-positive, HR-positive, triple-negative or BRCA mutation can be devastating — even for the most resilient person. Simply put, all are linked to breast cancer. Breast cancer is complex, and a diagnosis can be caused by all, some, or even none of the factors listed above.

Emily Burke, BiotechPrimer.com

Emily Burke, BiotechPrimer.com

In fact, the National Cancer Institute’s annual report to the nation outlined four molecular subtypes of the disease. Each subtype is categorized by the cancer’s hormone receptor (HR) status and the level of expression from the HER2 gene. These cellular distinctions lead patients on different treatment journeys because the cancer subtype determines the drugs used in a treatment plan.

HER2-Positive

HER2-positive (HER2+) breast cancer patients — about 20% of all breast cancer cases — have the most highly effective therapies available on the market. HER2+ cancer cells produce, and therefore present, larger than normal numbers of the HER2 receptors on their cell surface. These HER2 receptors capture growth factors, which trigger the cell to grow and reproduce more rapidly than normal. Mutations are more likely with rapid reproduction and thus, a tumor is born.

Overexpression of the HER2 receptor is the result of having extra copies of the HER2 gene, known in the world of genomics as gene amplification. Gene amplification events are thought to be caused by mutations that occur after a person is born — it is not an inherited form of cancer.

Certain monoclonal antibodies can bind to and block the activity of the HER2 receptor on cancer cells. When the HER2 receptor is blocked, the HER2 growth factor can no longer bind and send a growth signal to the cell, so the cancer cells stop dividing. The presence of an antibody on the surface of HER2+ breast cancer cells also signals the patient’s immune system to attack the cell.

Another available treatment comes in the form of an antibody-drug conjugate — a monoclonal antibody that delivers a highly toxic drug directly to HER2+ breast cancer cells. As a normal part of the cell’s lifecycle, cell-surface receptors get internalized or “taken up” by the cell on a regular basis. When the antibody-drug conjugate is attached to a receptor that gets internalized, the toxic payload is released from the antibody and kills the cancer cell internally.

HR-Positive

About 70% of breast cancer diagnoses involve a significant number of receptors for either estrogen or progesterone, making them hormone receptor positive (HR+). HR+ cancers may respond positively to treatments that block either the action or the production of estrogen. In some cases, these treatments may continue to be used for up to five years after initial treatment to prevent recurrence.

Two common type of medications for HR-positive breast cancers are tamoxifen and aromatase inhibitors. Both types of drugs may also be prescribed as a preventative treatment in women who are at high risk for breast cancer. In fact, tamoxifen is named on the World Health Organization’s List of Essential Medicines, a list of the most important medications needed in a basic healthcare system.

Tamoxifen works by inhibiting the estrogen receptor. On the other hand, aromatase inhibitors block the production of estrogen by inhibiting an enzyme whose activity is required for estrogen production.

In February of this year, the FDA approved a new treatment for estrogen-receptor positive, HER2-negative breast cancer: a small molecule inhibitor of cellular enzymes known as cyclin-dependent kinases (CDKs). CDKs promote the development and division of cancer cells, and inhibiting CDKs helps to arrest cancer growth.

Triple-Negative

Triple-negative breast cancers lack receptors — they are estrogen-receptor negative, progesterone-receptor negative, and HER2-negative. Since there are no receptor drug targets, this subtype is challenging to treat, and to date there are no targeted therapeutics. If detected early enough, triple-negative breast cancer may respond well to chemotherapy.

The BRCA Gene

BRCA stands for “BReast CAncer susceptibility gene” and everyone has the BRCA1 and BRCA2 genes. The job of BRCA is to scan cellular DNA for damage and trigger DNA repair processes when mutations are found. BRCA genes are passed down from one generation to the next — a good thing, unless the version passed down is a mutated version.

Mutated BRCA1/2 genes are non-functioning, so they cannot locate DNA damage, nor can they enlist DNA repair. Testing positive for BRCA1/2 mutations may indicate there is an accumulation of DNA damage, which may eventually lead to cancer. BRCA is normally active in breast and ovarian cells, which is why certain mutations in BRCA1/2 are associated with a significantly increase risk of developing breast or ovarian cancer. It must be stressed that BRCA1/2 mutations in and of themselves do not cause cancer; they simply make it more likely to occur.

A new class of drugs known as PARP1 inhibitors gives hope to patients whose breast cancer is associated with non-functioning BRCA genes. PARP1 is a second type of DNA repair protein. By inhibiting this pathway, DNA damage becomes so extensive that the cancer cells commit “cell suicide” (or apoptosis). When the cell in question is a cancerous cell, apoptosis is a very good outcome.

Not all triple-negative breast cancers are BRCA associated, but many BRCA associated cancers are triple-negative. For this reason, triple-negative breast cancer patients may find hope in PARP1 inhibitor drugs.

 

Personalized Medicine & Companion Diagnostics: What You Need to Know

Personalized medicine – also referred to as precision or stratified medicine – is already changing the way we diagnose and treat disease. As our ability to obtain and analyze large amounts of genetic data increases, so too will the range and power of these personalized tools.

Emily Burke, BiotechPrimer.com

Emily Burke, BiotechPrimer.com

The idea of personalized medicine is not new. Physicians have long known that patients vary in their responses to medicine, and have sought to optimize individual responses. The father of medicine, Hippocrates, writing more than two millennia ago, said “It is more important to know what sort of person has a disease,” wrote Hippocrates, “than to know what sort of disease a person has.”  But today, for the first time in human history, we have the tools available to make it personalized medicine a reality.

Twenty years ago, there were only four medicines on the market with genomic information on their label. Today, there are more than 100. These breakthroughs were made possible first by the completion of the Human Genome Project in 2003, and accelerated by advances in technology that have made sequencing individual patient genomes a realistic possibility. These new medicines and their accompanying diagnostics have increased both safety and efficacy by targeting specific patient populations most likely to benefit.

In this Real World Health Care series, we’ll examine specific examples of personalized medicines and diagnostics, and explain the technology that has made them possible.

Helpful Terms

Companion Diagnostic: A companion diagnostic is the test or measurement intended to assist physicians in making treatment decisions for their patients, usually by determining the efficacy and/or safety of a specific drug for a targeted patient group. For a list of all FDA-approved companion diagnostics, click here.

DNA Sequencing: Determines the order of every single base pair in a given gene (gene sequencing) or in an entire genome (whole genome sequencing).

Epidermal Growth Factor Receptors (EGFR): EGFR is found on the cell surface and is activated by growth factor binding. Once activated, EGFR activates enzymes inside the cell that drive the cell forward into cell division. EGFR overexpression is associated with a number of cancers, including lung cancer, anal cancers, and glioblastoma multiforme.

Gene Expression: The process cells use to read genetic information to make proteins. Because each cell in our body has the same genetic information, it is the differences in gene expression that determine what proteins a cell will end up producing. Gene expression differences are also associated with disease. For example, a type of cell or tissue may make too much or too little of a particular protein, which is the basis for many genetic disorders.

Monogenic Diseases: Changes in one gene cause the disease. Examples: sickle cell anemia, cystic fibrosis, and Huntington’s disease.

Personalized Medicine: Implies the development of medicines for an individual, based on their unique genetic, metabolic, microbiomic and other “signatures.”

Pharmacodynamics (PD): How a drug affects the body.

Pharmacokinetics (PK): How the body affects a drug.

Polygenic Disease: Caused by the interactions of many different genes. Examples: cancer, heart disease, Alzheimer’s disease and Parkinson’s disease. Polygenic diseases often have susceptibility genes associated with them, which increase the likelihood of the person developing the disease, but do not absolutely predict its development.

Precision Medicine: Dividing patient groups into specific populations and designing new drugs for those subtypes.

Prodrug: A drug given to patients in an inactive or less than fully active form.

Single Nucleotide Polymorphism (SNP): A one base difference in the DNA sequence of a gene when compared to the sequence found in the majority of the population. Many SNPs have no significant impact on an individual’s health, but others are associated with disease susceptibility.

Check back soon for the next article in our series on personalized medicine and companion diagnostics: an interview with Joshua P. Cohen, Ph.D., Research Associate Professor, Tufts Center for the Study of Drug Development.

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