War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert

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War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert

March 27, 2015 by sjwilliamspa

War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert

Writer, Curator: Stephen J. Williams, Ph.D.

Article ID #171: War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert. Published on 3/27/2015

WordCloud Image Produced by Adam Tubman

UPDATED 1/08/2020

Is one of the world’s most prominent cancer researchers throwing in the towel on the War On Cancer? Not throwing in the towel, just reminding us that cancer is more complex than just a genetic disease, and in the process, giving kudos to those researchers who focus on non-genetic aspects of the disease (see Dr. Larry Bernstein’s article Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?).

National Public Radio (NPR) has been conducting an interview series with MIT cancer biology pioneer, founding member of the Whitehead Institute for Biomedical Research, and National Academy of Science member and National Medal of Science awardee Robert A. Weinberg, Ph.D., who co-discovered one of the first human oncogenes (Ras)[1], isolation of first tumor suppressor (Rb)[2], and first (with Dr. Bill Hahn) proved that cells could become tumorigenic after discrete genetic lesions[3]. In the latest NPR piece, Why The War On Cancer Hasn’t Been Won (seen on NPR’s blog by Richard Harris), Dr. Weinberg discusses a comment in an essay he wrote in the journal Cell[4], basically that, in recent years, cancer research may have focused too much on the genetic basis of cancer at the expense of multifaceted etiology of cancer, including the roles of metabolism, immunity, and physiology. Cancer is the second most cause of medically related deaths in the developed world. However, concerted efforts among most developed nations to eradicate the disease, such as increased government funding for cancer research and a mandated ‘war on cancer’ in the mid 70’s has translated into remarkable improvements in diagnosis, early detection, and cancer survival rates for many individual cancer. For example, survival rate for breast and colon cancer have improved dramatically over the last 40 years. In the UK, overall median survival times have improved from one year in 1972 to 5.8 years for patients diagnosed in 2007. In the US, the overall 5 year survival improved from 50% for all adult cancers and 62% for childhood cancer in 1972 to 68% and childhood cancer rate improved to 82% in 2007. However, for some cancers, including lung, brain, pancreatic and ovarian cancer, there has been little improvement in survival rates since the “war on cancer” has started.

(Other NPR interviews with Dr. Weinberg include How Does Cancer Spread Through The Body?)

As Weinberg said, in the 1950s, medical researchers saw cancer as “an extremely complicated process that needed to be described in hundreds, if not thousands of different ways,”. Then scientists tried to find a unifying principle, first focusing on viruses as the cause of cancer (for example rous sarcoma virus and read Dr. Gallo’s book on his early research on cancer, virology, and HIV in Virus Hunting: AIDS, Cancer & the Human Retrovirus: A Story of Scientific Discovery).

However (as the blog article goes on) “that idea was replaced by the notion that cancer is all about wayward genes.”

“The thought, at least in the early 1980s, was that were a small number of these mutant, cancer-causing oncogenes, and therefore that one could understand a whole disparate group of cancers simply by studying these mutant genes that seemed to be present in many of them,” Weinberg says. “And this gave the notion, the illusion over the ensuing years, that we would be able to understand the laws of cancer formation the way we understand, with some simplicity, the laws of physics, for example.”

According to Weinberg, this gene-directed unifying theory has given way as recent evidences point back once again to a multi-faceted view of cancer etiology.

But this is not a revolutionary or conflicting idea for Dr. Weinberg, being a recipient of the 2007 Otto Warburg Medal and focusing his latest research on complex systems such as angiogenesis, cell migration, and epithelial-stromal interactions.

In fact, it was both Dr. Weinberg and Dr. Bill Hanahan who formulated eight governing principles or Hallmarks of cancer:

Maintaining Proliferative Signals
Avoiding Immune Destruction
Evading Growth Suppressors
Resisting Cell Death
Becoming Immortal
Angiogenesis
Deregulating Cellular Energy
Activating Invasion and Metastasis

Taken together, these hallmarks represent the common features that tumors have, and may involve genetic or non-genetic (epigenetic) lesions … a multi-modal view of cancer that spans over time and across disciplines. As reviewed by both Dr. Larry Bernstein and me in the e-book Volume One: Cancer Biology and Genomics for Disease Diagnosis, each scientific discipline, whether the pharmacologist, toxicologist, virologist, molecular biologist, physiologist, or cell biologist has contributed greatly to our total understanding of this disease, each from their own unique perspective based on their discipline. This leads to a “multi-modal” view on cancer etiology and diagnosis, treatment. Many of the improvements in survival rates are a direct result of the massive increase in the knowledge of tumor biology obtained through ardent basic research. Breakthrough discoveries regarding oncogenes, cancer cell signaling, survival, and regulated death mechanisms, tumor immunology, genetics and molecular biology, biomarker research, and now nanotechnology and imaging, have directly led to the advances we now we in early detection, chemotherapy, personalized medicine, as well as new therapeutic modalities such as cancer vaccines and immunotherapies and combination chemotherapies. Molecular and personalized therapies such as trastuzumab and aromatase inhibitors for breast cancer, imatnib for CML and GIST related tumors, bevacizumab for advanced colorectal cancer have been a direct result of molecular discoveries into the nature of cancer. This then leads to an interesting question (one to be tackled in another post):

Would shifting focus less on cancer genome and back to cancer biology limit the progress we’ve made in personalized medicine?

In a 2012 post Genomics And Targets For The Treatment Of Cancer: Is Our New World Turning Into “Pharmageddon” Or Are We On The Threshold Of Great Discoveries? Dr. Leonard Lichtenfield, MD, Deputy Chief Medical Officer for the ACS, comments on issues regarding the changes which genomics and personalized strategy has on oncology drug development. As he notes, in the past, chemotherapy development was sort of ‘hit or miss’ and the dream and promise of genomics suggested an era of targeted therapy, where drug development was more ‘rational’ and targets were easily identifiable.

To quote his post

“

That was the dream, and there have been some successes–even apparent cures or long term control–with the used of targeted medicines with biologic drugs such as Gleevec®, Herceptin® and Avastin®. But I think it is fair to say that the progress and the impact hasn’t been quite what we thought it would be. Cancer has proven a wily foe, and every time we get answers to questions what we usually get are more questions that need more answers. The complexity of the cancer cell is enormous, and its adaptability and the genetic heterogeneity of even primary cancers (as recently reported in a research paper in the New England Journal of Medicine) has been surprising, if not (realistically) unexpected.

”

Indeed the complexity of a given patient’s cancer (especially solid tumors) with regard to its genetic and mutation landscape (heterogeneity) [please see post with interview with Dr. Swanton on tumor heterogeneity] has been at the forefront of many clinicians minds [see comments within the related post as well as notes from recent personalized medicine conferences which were covered live on this site including the PMWC15 and Harvard Personalized Medicine conference this past fall].

In addition, Dr. Lichtenfeld makes some interesting observations including:

A “pharmageddon” where drug development risks/costs exceed the reward so drug developers keep their ‘wallets shut’. For example even for targeted therapies it takes $12 billion US to develop a drug versus $2 billion years ago
Drugs are still drugs and failure in clinical trials is still a huge risk
“Eroom’s Law” (like “Moore’s Law” but opposite effect) – increasing costs with decreasing success
Limited market for drugs targeted to a select mutant; what he called “slice and dice”

The pros and cons of focusing solely on targeted therapeutic drug development versus using a systems biology approach was discussed at the 2013 Institute of Medicine’s national Cancer Policy Summit.

Andrea Califano, PhD – Precision Medicine predictions based on statistical associations where systems biology predictions based on a physical regulatory model
Spyro Mousses, PhD – open biomedical knowledge and private patient data should be combined to form systems oncology clearinghouse to form evolving network, linking drugs, genomic data, and evolving multiscalar models
Razelle Kurzrock, MD – What if every patient with metastatic disease is genomically unique? Problem with model of smaller trials (so-called N=1 studies) of genetically similar disease: drugs may not be easily acquired or re-purposed, and greater regulatory burdens

So, discoveries of oncogenes, tumor suppressors, mutant variants, high-end sequencing, and the genomics and bioinformatic era may have led to advent of targeted chemotherapies with genetically well-defined patient populations, a different focus in chemotherapy development

… but as long as we have the conversation open I have no fear of myopia within the field, and multiple viewpoints on origins and therapeutic strategies will continue to develop for years to come.

References

Parada LF, Tabin CJ, Shih C, Weinberg RA: Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 1982, 297(5866):474-478.
Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP: A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986, 323(6089):643-646.
Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA: Creation of human tumour cells with defined genetic elements. Nature 1999, 400(6743):464-468.
Weinberg RA: Coming full circle-from endless complexity to simplicity and back again. Cell 2014, 157(1):267-271.

UPDATED 1/08/2020

from the Washington Post

Cancer death rate posts biggest one-year drop ever

The 2.2 percent decline in 2017 is part of a long-term decrease in mortality rates.

Laurie McGinley

Jan. 8, 2020 at 7:00 a.m. EST

The cancer death rate in the United States fell 2.2 percent in 2017 — the biggest single-year drop ever reported — propelled by gains against lung cancer, the American Cancer Society said Wednesday.

Declines in the mortality rate for lung cancer have accelerated in recent years in response to new treatments and falling smoking rates, said Rebecca Siegel, lead author of Cancer Statistics 2020, the latest edition of the organization’s annual report on cancer trends.

The improvement in 2017, the most recent year for which data is available, is part of a long-term drop in cancer mortality that reflects, to a large extent, the smoking downturn. Since peaking in 1991, the cancer death rate has fallen 29 percent, which translates into 2.9 million fewer deaths.

Norman “Ned” Sharpless, director of the National Cancer Institute, which was not involved in the report, said the data reinforces that “we are making steady progress” on cancer. For lung cancer, he pointed to new immunotherapy treatments and so-called targeted therapies that stop the action of molecules key to cancer growth. He predicted that the mortality rate would continue to fall “as we get better at using these therapies.” Multiple clinical trials are exploring how to combine the new approaches with older ones, such as chemotherapy.

Sharpless expressed concern, however, that progress against cancer would be undermined by increased obesity, which is a risk factor for several malignancies.

The cancer society report projected 1.8 million new cases of cancer in the United States this year and more than 606,000 deaths. Nationally, cancer is the second-leading cause of death after heart disease in both men and women. It is the No. 1 cause in many states, and among Hispanic and Asian Americans and people younger than 80, the report said.

The cancer death rate is defined as deaths per 100,000 people. The cancer society has been reporting the rate since 1930.

Because lung cancer is the leading cause of cancer deaths, accounting for 1 in 4, any change in the mortality rate has a large effect on the overall cancer death rate, Siegel noted.

She described the gains against lung cancer, and against another often deadly cancer, melanoma, as “exciting.” But, she added, “the news this year is mixed” because of slower progress against colorectal, breast and prostate cancers. Those cancers often can be detected early by screening, she said.

The report said substantial racial and geographic disparities remain for highly preventable cancers, such as cervical cancer, and called for “the equitable application” of cancer control measures.

The five-year survival rate for all cancers diagnosed from 2009 through 2015 was 67 percent overall — 68 percent for whites and 62 percent for African Americans.

In recent years, melanoma has showed the biggest mortality-rate drop of any cancer. That’s largely a result of breakthrough treatments such as immunotherapy, which unleashes the patient’s own immune system to fight the cancer and was approved for advanced melanoma in 2011.