NYCRCS&SG The following presentation was given on March 10th, - - PowerPoint PPT Presentation

The following presentation was given on March 10th, 2018 in Holbrook, NY, during the annual luncheon of the NYCRCS&SG. The presentation illustrates that cancer is eminently a cellular disease, the role that growth and death rates of normal and malignant cells play in the rationale behind debulking surgery, current adjuvant chemotherapy and prospects for personalized adjuvant cancer chemotherapy. Dr. Miguel Berrios, earned his Ph.D. in cell biology from The Rockefeller University receiving post graduate training at Weill Cornell Medical College and The State University of New York. Dr. Berrios conducted basic cancer research for about 30 years, he is currently Professor Emeritus at Stony Brook University.

• Dr. Berrios suffers from colorectal cancer, is a patient of Dr. Roberto Bergamaschi and

member of the NYCRCS&SG. Thank you. Michael Killarney, President NYCRCS&SG

• Dr. Roberto Bergamaschi, MD, PhD, FRCS, FASCRS, FACS

Founder, NYCRCS&SG

NYCRCS&SG

Colorectal Cancer: The Biology

• f Adjuvant Chemotherapy

Miguel Berrios, Ph.D.

NYCRCS&SG

Cancer, the “King” of all diseases, produces fear in us. Besides being difficult to accept, it causes a condition in which our own cells deregulate themselves becoming “terrorist guerrillas” whose only purpose is to divide and along the way cause organ failure and eventually death. In contrast to autoimmune diseases, in which cells belonging to our own immune system (a hierarchical organized system), also attack our organs for destruction. Malignant cells lack a recognized hierarchy nor are they regulated. As a result, chemotherapy has proven much more successful fighting autoimmune diseases than when used to fighting cancer. However, not all is gloom and doom when it comes to fighting cancer. In the near future, immunotherapies, biological response modifiers as well as investigative anti-cancer agents combined with cloud-based databases and supercomputers, will result in the introduction of personalized cancer chemotherapies (including for colorectal cancer) that will prove to be highly effective while carrying little side effects. Thus, cancer will become a chronic condition, rather than sometimes a lethal disease.

• About 66% to 75% of mutations

that cause cancer are due to random DNA (copy) errors.

• The reminder cancers are caused

by genetic predisposition, life- style, environment, etc.

Normal vs. Cancer Cells

• Normal cells are highly regulated. They use a combination of

sentinels, checkpoints and repair systems to prevent genetic instability and selection. Moreover, if any of these regulatory mechanisms fail, they have the ability for programmed cell death. Normal cells are mortal.

• Cancer or malignant cells develop through a combination of

genetic instability and selection. This results in the proliferation

• f (malignant) cells that have accumulated and advantageous set
• f genetic aberrations. These aberrations may act alone or in

concert to alter the function or expression of cellular components and/or processes. Cancer cells are immortal.

The Cell Cycle

• Solid tumors have a low “growth fraction.”
• Disseminated tumors have a high “growth fraction.”

Tumors vs. Cancer Chemotherapy

• A tumor’s growth fraction is

the ratio between dividing and non-dividing cells.

• Chemotherapeutic drugs are

more toxic to tumors with high “growth fraction” than with low “growth fraction.”

• Drugs vs. poisons
• Therapeutic index
• Selective toxicity

Cancer Chemotherapy

Cytotoxic Drugs:

• Alkylating agents
• Platinum compounds*
• Antimetabolites*
• Antitumor antibiotics
• Mitotic inhibitors
• DNA Topoisomerase inhibitors

Other Drugs:

• Drugs for breast and prostate cancer
• Targeted drugs
• Immunotherapies (active, passive or hybrid)
• Biologic response modifiers (BRM)
• Drugs for cancer prevention

Cancer Chemotherapy: Drug Families

Obstacles to Successful Chemotherapy

• Early detection of cancer is rare. Smallest directly detectable

tumor is about 1g (or a tumor containing 108 to 109 cells).

• Chemotherapeutic drugs lack selective toxicity limiting their

administration.

• Cancer cell killing follows 1st order kinetics.
• Cancer cure requires 100% cancer cell kill.
• Minimal participation of the immune system in killing cancer

cells.

• Symptoms disappear before all cancer cells are killed or removed.

Strategies for Achieving Maximum Benefits from Cancer Chemotherapy

• Tumor debulking surgery
• Intermittent chemotherapy
• Combination chemotherapy

Drug combination requirements:

✓ Each drug has to be effective by itself ✓ Each drug should have different mechanism of action ✓ Drugs should have no or minimally overlapping toxicities

Combination Cancer Chemotherapy:

(e.g., FOLFOX)

(1) Folinic acid (Leucovorin) -- Synergistically enhances the

effects of fluorouracil by inhibiting the enzyme thymidylate synthase.

(2) Fluorouracil -- Fluorinated derivative of uracil inhibiting DNA

replication.

(3) Oxilaplatin -- Generates cross-links inhibiting DNA replication and

transcription.

(4) Antiemetics -- Inhibit chemotherapy-induced nausea and vomiting

Time Number of live cells

10 9 10 6 Normal cells Cancer cells Patient’s death due to cancer Earliest tumor detection limit Patient’s symptoms appear

Time Number of live cells

10 9 10 6 Normal cells Cancer cells

Daily (continuous) cancer chemotherapy treatments

Patient’s death caused by cancer and/or “death by chemotherapy” Cancer cell resistance appears Patient’s symptoms appear

Time Number of live cells

10 9 10 6 Normal cells Cancer cells Surgical removal

• f tumor

Bi-weekly chemotherapy Patient’s symptoms appear

Time Number of live cells

10 9 10 6 Normal cells Cancer cells

Surgical removal of tumor

Bi-weekly chemotherapy (FOLFOX)

Patient’s symptoms appear Earliest tumor detection limit Cancer cells that eluded or hide from and/or became resistant to cancer chemotherapy

months to years

Patient’s symptoms appear

Diagnosis: Colorectal Cancer (early detection, e.g., 102 - 104 cells)

Colorectal Cancer: Therapy Prospects

Tumor debulking by colorectal cancer surgeon

Genetic Testing Tumor biopsy is evaluated genetically & for expression

Interim, short term systemic chemotherapy

Genetic & expression information, sent to world-wide cloud-based databases

Oncologist discusses therapy

• ptions with patient

Supercomputers search databases for best therapeutic

• ptions

Tumor-specific immunotherapies + Investigative & tumor-specific biological response modifiers

Patient recovers quickly with few mild side effects

Patient is regularly monitored via biochemical profiling, tumor markers and CT scans Patient’s colorectal cancer is under control or eliminated. Colorectal cancer becomes a chronic condition or disease.