Jim Olson is a paediatric oncologist whose research is being talked about around the world thanks to some innovative thinking – and scorpions. Based at the Fred Hutchinson Cancer Research Center in Seattle, he leads a team whose biggest success is “tumour paint”, a drug that attaches to cancer cells, lighting them up so it is easier for surgeons to operate successfully.
The paint was developed from chlorotoxin found in scorpion venom and is currently being tested in clinical trials. So excited was Olson, 52, by this discovery that he had the knot of bonds at the centre of the chlorotoxin molecule tattooed on his upper arm. Decorating his office are framed photographs of his patients at Seattle Children’s Hospital, who are clearly the motivation for his work: he is driven by a desire to tell more parents their children will survive.
His quiet, unassuming manner belies the passion and energy with which Olson approaches life – both at work and in his leisure time when he cooks, cycles and kayaks (his team won a national title in 2012) with gusto.
He remains close to many of the families he meets and is a tireless campaigner, successfully using social media and crowdfunding to publicise and raise money for his research. Your biggest success is “tumour paint”, which makes cancer cells easier to spot during brain surgery and is now in five human clinical trials. How was this developed? We had a patient who had brain tumour surgery in 2004, which left much of her tumour behind because the surgeon thought it was normal brain and didn’t want to paralyse her. When we realised how much was left behind and the problem for the surgeon not being able to easily distinguish cancer from normal brain, we committed to developing a technology that would light up the cancer. We focused on the scorpion toxin chlorotoxin, because what was thought to be the target of that molecule was present on brain tumour cells but not on brain cells. I figured that if there was ever a creature that could get a molecule into the brain, it would be the scorpion because they need to paralyse their prey. So we grew a human tumour on the back of a mouse; we connected the toxin (from the deathstalker scorpion) to a fluorescent tag and injected it into the mouse, and a couple of hours later the cancer was brightly glowing. It was a very exciting day.
As well as lighting them up, can this scorpion molecule also deliver chemotherapy drugs to tumours? This wouldn’t be the right molecule to do that because a fair amount of it also goes to the liver and the spleen. If we put a toxin on it, it would also wipe out those normal organs. Through our current research we’ve identified a different molecule from a different organism – a grasshopper – that goes to cancer but much less to the liver and spleen. That’s the foundation for our future work.
Does tumour paint work for other cancers? In prior work, the tumour paint molecule, known as BLZ-100, lit up a variety of cancers in dogs. Now scientists at Blaze Bioscience [the spin-off company co-founded by Olson which is running the ongoing human clinical trials] have reported that in skin cancer patients, the BLZ-100 signal was present in nearly all cases of confirmed cancer and was absent in most cases where the pathologist determined that the skin lesion was not cancer.
What is the difference between tumour paint and fluorescent imaging with 5-ALA that is approved for use in Europe but not the United States? With 5-ALA surgeons can often get a better resection and patients a better outcome than without it. It does have some limitations. When there’s a brain tumour and the blood-brain barrier (which keeps nasty things out of our brain) is disrupted, the 5-ALA will get in there and light up that area. The challenge is that sometimes there are parts of the tumour where the blood-brain barrier is not interrupted, it’s intact, and so those don’t light up with 5-ALA. We set out to find a molecule that crosses the blood-brain barrier so it could light up tumours either way, whether the blood-brain barrier is intact or not, and where the drug actually binds to each cancer cell and goes inside the cancer cell and makes them glow so that surgeons can see cell by cell. We hope it will be much more accurate.
What drives your work? Each week when I go to clinic, I ask myself: “What are we going to do today that I don’t want to be doing in 20 years, and how can my lab play a role in changing that?”
Why did you decide to go into paediatric oncology? I took care of a little girl who passed away. Her parents told me that my words with them made her death as beautiful as her birth and that through the conversations we’d had, they’d learned that a life could be seven years long or 70 years long and what mattered was the beauty of what occurred during that time. I thought I had something to offer when the medicine didn’t go the way you wanted it to.
There are many photographs of children you have cared for in your office. How do you cope with the emotional side of your work? I realised early on that I was going to suffer and be in pain when these kids passed away or weren’t doing well whether I chose to compartmentalise it or not. I decided to go all in and fully love each kid and each family and to become part of that family the day we meet. You can take extraordinary ups and downs when you are part of a family. I stay close to many of them.
Do you have children? I’ve got two daughters, 21 and 17. They are both wonderful writers, activists and feminists. My older daughter is head of the animal rights group at the University of Washington so you’d think there’d be a big clash, but she did a TEDx talk last year and she wove our work together. My team tries to minimise the use of animals and importantly we’re very open to using alternatives when the alternatives are useful and accessible. Her point is that similar investments should be put into finding alternatives to animal testing as to continuing the status quo. We have very good and respectful conversations.
Is it frustrating that it takes so long to bring a new drug to market? Well, it is – take tumour paint as an example. My own mother had a cancer that would definitely have benefited from it and it was too early to use it. It started in the skin on her face and went back into her brain. It ended up spreading extensively and that could have been avoided if it had been understood that they hadn’t got it all and had gone a little bit deeper. She’s doing fine now, two years later. I love my patients in the same way, so every week when we have kids, and we can’t use it yet… These things just take time though. The reality is that if things move forward too fast you can have really serious safety problems. I don’t get frustrated because frustration doesn’t help you move forward.
How do you fund your research? Most innovative ideas are really hard to get approved through peer review [and therefore funded by grants] … so the families stepped up by doing chilli cook-offs, golf tournaments and auctions and they’ve raised over $10m since the late 90s. In 2013 we launched Project Violet. We’re well past $5m with that.
Tell me about Project Violet. We decided to build a platform where we could identify other similar molecules [to the tumour paint molecule] that plants and animals use for protection in nature, and find a way to create hundreds of thousands of variations of these that could be used for screening for human diseases. I realised that to do this we were going to need to build a team of experts. We launched Project Violet so we could use social media and the public domain to co-operatively build these libraries of drug candidates. I launched that in my TEDx talk in June 2013 and since then we’ve been able to support, or partially support, 33 scientists. For a year around that, volunteers from Amazon here in Seattle helped us build our website and our social media presence.
Violet was a little girl who had a type of brain tumour that I’ve not yet had a child survive. She knew she was going to die. She decided to donate her tissue when she died to help other children. Also, some of these molecules we’re working on come from the violet plant. Any other research successes? One day, I realised I was prescribing medicines with no idea whether the cancer would be resistant to that drug. So, I hired two bioengineers and we created a technology where needles are exerted through the skin into a tumour and as the needles are withdrawn they leave behind tracks of different drugs. You let those drugs be present around the tumour cells a day or so, then take out the tumour and cut across-wise to the needles and see which ones work and which don’t. If a drug doesn’t kill any cancer cells when they are bathed in it, it certainly isn’t going to get any better when you give that drug as an IV or by mouth. I think this is going to revolutionise cancer and drug development.
Hedgehog pathway inhibitors exciting development in treating non-melanoma skin cancer
In the treatment of non-melanoma skin cancer, “the fastest-moving area—and the neatest from a science standpoint—is the class of drugs called hedgehog pathway inhibitors.”
That’s the message Scott Dinehart, M.D., delivered in his presentation, “Medical Advances in Non-Melanoma Skin Cancer,” yesterday (Thursday, Oct. 1), the opening day of the Fall Clinical Dermatology Conference in Las Vegas.
Dr. Dinehart, a Little Rock, Ark., dermatologist, says hedgehog pathway inhibitors are approved for certain patients with basal cell carcinoma.
“The average dermatology practitioner will not use these molecules on a daily basis, however, the medications are very useful for a small subset of patients for which other treatments are not optimal,” he says. “Using this class of medications requires knowledge and experience and can be extremely satisfying from both a practitioner and a patient viewpoint.”
According to Dr. Dinehart, some common medications with which dermatologists are already familiar and comfortable are hedgehog pathway inhibitors—the anti-fungal drug itraconazole and imiquimod are examples. What excites him are advances in putting this class of drugs to work.
“There are new ways to use hedgehog pathway inhibitors—continuously, intermittently, shrinking a tumor prior to surgery, in combination—so that the hedgehog pathway is blocked in more than one part of the pathway,” he says.
Dr. Dinehart believes more such advances are in store for these drugs.
“We will continue to see more innovative ways to use hedgehog pathway inhibitors in skin cancer patients,” he says. “Combination or dual therapy with multiple hedgehog pathway inhibitors is something that may increase efficacy and diminish resistance. We will see more research on this in the future.”
The presence of multiple squamous-cell skin cancer lesions significantly increased the likelihood of local recurrence and lymph node metastasis, a retrospective cohort study showed.
As compared with a single lesion, two to nine squamous-cell cancers almost doubled the risk of local recurrence and tripled the likelihood of nodal invasion. The few patients who had 10 or more lesions, most of whom were immuno suppressed, had a fourfold greater risk of local recurrence and nodal metastasis.
Although the absolute risk associated with multiple squamous-cell skin cancers remained modest, the findings emphasize the need for frequent follow-up, Chrysalyne D. Schmults, MD, of Brigham and Women's Hospital in Boston, and colleagues concluded in an article published online in JAMA Dermatology.
"These findings substantiate the importance of close follow-up for dermatologic patients with multiple cutaneous squamous-cell carcinomas (CSCCs), especially those with many tumors, and highlight the necessity for dermatologists to document prior CSCC sites, examine the scar sites of prior CSCCs, and perform lymph node examinations in those patients," the authors concluded. "Larger studies are required to determine which factors affect multiple tumor formation and subsequent outcomes."
The findings reflect a clinical scenario analogous to Russian roulette: "The more 'bullets in the chamber,' the higher the risk for local recurrence and spread to local lymph nodes," said Dominic Ricci, MD, of Baylor Scott & White Healthcare in Round Rock, Texas.
"The surprising thing, however, was that this high risk existed even if the original tumors weren't particularly aggressive," Ricci, who wasn't involved in the study, told MedPage Today in an email.
"Follow-up is extremely important for these patients," he added. "For patients with more than 10 cutaneous squamous cell carcinomas, they should be seen probably every 3 to 4 months by a dermatologist, and their exam should include a check of the lymph nodes in the region of their skin cancers. For patients with two to nine lesions -- depending on over what time period the skin cancers have occurred -- they should probably been seen every 6 months, at least yearly."
Despite the well-documented association between sun exposure and skin cancer, an estimated 400,000 to 700,000 new cases of CSCC arise each year in the United States, second only to basal-cell skin cancer. Although most cases are curable, patients do die of CSCC, with the estimated annual mortality ranging from 4,000 to 8,800 cases. In some parts of the southern and central U.S., deaths attributable to CSCC may exceed the number of deaths caused by other types of cancer, including melanoma.
Large cohort studies have identified factors associated with poor outcome in CSCC: larger tumor diameter, depth of invasion, poor differentiation, perineural invasion, lymphovascular invasion, desmoplasia, immunosuppression, and location on the ear, temple, or lip.
By the Brigham and Women's Hospital (BWH) tumor staging system, the presence of two or more risk factors define high-stage CSCC, conferring an elevated risk of nodal metastases and death. The staging system comprises diameter ≥2 cm, tumor invasion beyond subcutaneous fat, poorly differentiated histologic features, and large-caliber nerve invasion ≥0.1 mm.
A few studies have examined the risk of subsequent CSCC formation in patients with a history of the lesions, the authors continued. However, only a single study has examined the impact of lesion number on subsequent risk and outcomes, and that investigation employed a cutoff of three or more lesions versus fewer than three.
"There are no studies, to our knowledge, that specifically evaluate CSCC outcomes in individuals who form multiple versus single CSCCs," Levine and colleagues noted in their introduction.
To address the risk of multiple versus single CSCC lesions, investigators searched an electronic medical record database to identify patients treated for "dermally invasive (non-in situ) primary CSCC" from Jan. 1, 2000 through Dec. 31, 2009. The query identified 985 patients: 727 who had one CSCC, 239 who had two to nine lesions, and 19 who had 10 or more CSCCs. All but four of the patients with 10+ lesions were immunosuppressed.
The primary outcomes of interest were local recurrence (LR) and nodal metastasis (NM). During a median follow-up of 50 months, patients with two to nine CSCCs had a risk of LR and NM of 1.8 times (95% CI 1.1-4.3) and 3.0 times greater (95% CI 1.4-6.5) than did patients with a single lesion. The small group of patients with 10 or more lesions had a subhazard ratio of 3.8 for LR (95% CI 1.4-10.0) and 4.2 for NM (95% CI 1.4-10.4).
The 10-year cumulative incidence of LR and NM increased with the number of CSCCs:
One CSCC - LR 3.0%, NM 2.3%
Two to nine - 6.7%, 5.9%
≥10 - 36.8%, 26.3%
CSCC-related mortality did not differ among patients with a single lesion (2.2%), two to nine lesions (2.0%), or ≥10 lesions (0%). Local recurrence and nodal metastasis were associated with higher tumor stage, irrespective of the number of lesions. Immunosuppression was significantly associated with high-stage tumors (P=0.04).
Authors of an invited review of the study, published online in JAMA Oncology, said the findings "confirm what is clinically intuitive -- that rates of local recurrence or nodal metastasis rise significantly as the number of CSCCs increases. The study's principal weakness -- acknowledged by the authors -- is that "increasing risk of poor outcomes in patients with multiple tumors may be merely an additive effect, as each additional CSCC is an independent event conferring additional risk," said Simon Yoo, MD, of Feinberg School of Medicine at Northwestern University in Chicago, and coauthors.
Source from : http://www.medpagetoday.com/Dermatology/SkinCancer/54032
Skin cancer — the abnormal growth of skin cells — most often develops on skin exposed to the sun. But this common form of cancer can also occur on areas of your skin not ordinarily exposed to sunlight.
There are three major types of skin cancer — basal cell carcinoma, squamous cell carcinoma and melanoma.
You can reduce your risk of skin cancer by limiting or avoiding exposure to ultraviolet (UV) radiation. Checking your skin for suspicious changes can help detect skin cancer at its earliest stages. Early detection of skin cancer gives you the greatest chance for successful skin cancer treatment.
Symptops:
Where skin cancer develops
Skin cancer develops primarily on areas of sun-exposed skin, including the scalp, face, lips, ears, neck, chest, arms and hands, and on the legs in women. But it can also form on areas that rarely see the light of day — your palms, beneath your fingernails or toenails, and your genital area.
Skin cancer affects people of all skin tones, including those with darker complexions. When melanoma occurs in people with dark skin tones, it's more likely to occur in areas not normally exposed to the sun, such as the palms of the hands and soles of the feet. Basal cell carcinoma signs and symptoms
Basal cell carcinoma usually occurs in sun-exposed areas of your body, such as your neck or face.
Basal cell carcinoma may appear as:
A pearly or waxy bump A flat, flesh-colored or brown scar-like lesion
Squamous cell carcinoma signs and symptoms
Most often, squamous cell carcinoma occurs on sun-exposed areas of your body, such as your face, ears and hands. People with darker skin are more likely to develop squamous cell carcinoma on areas that aren't often exposed to the sun.
Squamous cell carcinoma may appear as:
A firm, red nodule A flat lesion with a scaly, crusted surface
Melanoma signs and symptoms
Melanoma can develop anywhere on your body, in otherwise normal skin or in an existing mole that becomes cancerous. Melanoma most often appears on the face or the trunk of affected men. In women, this type of cancer most often develops on the lower legs. In both men and women, melanoma can occur on skin that hasn't been exposed to the sun.
Melanoma can affect people of any skin tone. In people with darker skin tones, melanoma tends to occur on the palms or soles, or under the fingernails or toenails.
Melanoma signs include:
A large brownish spot with darker speckles A mole that changes in color, size or feel or that bleeds A small lesion with an irregular border and portions that appear red, white, blue or blue-black Dark lesions on your palms, soles, fingertips or toes, or on mucous membranes lining your mouth, nose, vagina or anus
Signs and symptoms of less common skin cancers
Other, less common types of skin cancer include:
Kaposi sarcoma. This rare form of skin cancer develops in the skin's blood vessels and causes red or purple patches on the skin or mucous membranes.
Kaposi sarcoma mainly occurs in people with weakened immune systems, such as people with AIDS, and in people taking medications that suppress their natural immunity, such as people who've undergone organ transplants.
Other people with an increased risk of Kaposi sarcoma include young men living in Africa or older men of Italian or Eastern European Jewish heritage. Merkel cell carcinoma. Merkel cell carcinoma causes firm, shiny nodules that occur on or just beneath the skin and in hair follicles. Merkel cell carcinoma is most often found on the head, neck and trunk. Sebaceous gland carcinoma. This uncommon and aggressive cancer originates in the oil glands in the skin. Sebaceous gland carcinomas — which usually appear as hard, painless nodules — can develop anywhere, but most occur on the eyelid, where they're frequently mistaken for other eyelid problems.
When to see a doctor
Make an appointment with your doctor if you notice any changes to your skin that worry you. Not all skin changes are caused by skin cancer. Your doctor will investigate your skin changes to determine a cause.
Jim Olson is a paediatric oncologist whose research is being talked about around the world thanks to some innovative thinking – and scorpions. Based at the Fred Hutchinson Cancer Research Center in Seattle, he leads a team whose biggest success is “tumour paint”, a drug that attaches to cancer cells, lighting them up so it is easier for surgeons to operate successfully.
